[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 41

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: M886I | Summary: The mutation M886I is associated with cancer progression through altered binding to co-repressors or co-regulators, indicating its role in tumor development. Evidence Type: Functional | Mutation: M886I | Summary: The mutation M886I may not change activity from wild type but is suggested to alter molecular interactions, impacting its biochemical function.

Gene→Variant (gene-first): 9611:M886I

Genes: 9611

Variants: M886I

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 36

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: M749I | Summary: The M749I mutation demonstrates a significant loss of function in receptor activity, indicating its alteration of molecular function in the presence of DHT. Evidence Type: Oncogenic | Mutation: M749I | Summary: The M749I mutation has been identified in relapsed tumors and may contribute to prostate cancer progression, suggesting its role in tumor development. Evidence Type: Functional | Mutation: Q798E | Summary: The Q798E mutation shows a modest loss of function at low DHT levels but gains constitutive activity at higher levels, indicating an alteration in molecular function. Evidence Type: Oncogenic | Mutation: Q798E | Summary: The Q798E mutation's constitutive activity could have significant implications for prostate cancer development, suggesting its contribution to tumor progression. Evidence Type: Functional | Mutation: H874Y | Summary: The H874Y mutation exhibits increased constitutive activity and notable gains of function, indicating a change in molecular function that may influence receptor signaling. Evidence Type: Oncogenic | Mutation: H874Y | Summary: The H874Y mutation is associated with constitutive activity and promiscuous ligand activation, representing a potential driver of prostate cancer progression.

Gene→Variant (gene-first): 367:H874Y 1387:M749I 10514:Q798E

Genes: 367 1387 10514

Variants: H874Y M749I Q798E

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 35

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: T575A | Summary: The T575A mutation in the DBD alters the binding profile and transactivation activity, indicating a change in molecular function related to androgen receptor activity. Evidence Type: Functional | Mutation: R629Q | Summary: The R629Q mutation affects regulatory element activation and may interfere with acetylation of the 629RKLKK633 motif, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: I672T | Summary: The I672T mutation is predicted to disrupt the conformation of a protein-protein interaction surface, indicating a potential change in molecular function.

Gene→Variant (gene-first): 2908:I672 2908:I672T 10499:R629 10499:R629Q 10499:T575A

Genes: 2908 10499

Variants: I672 I672T R629 R629Q T575A

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 34

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: L57Q | Summary: The L57Q mutation exhibited loss of function at all concentrations of DHT, indicating an alteration in molecular function. Evidence Type: Oncogenic | Mutation: G142V | Summary: The G142V mutation demonstrated constitutive activity and gain of function in the presence of DHT, suggesting its role in tumor development. Evidence Type: Functional | Mutation: P390L | Summary: The P390L mutation represented a transition from loss of function to gain of function, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: P533S | Summary: The P533S mutation showed a transition from wild-type activity to gain of function, indicating an alteration in molecular function.

Gene→Variant (gene-first): 2232:G142V 367:L57Q 367:P390L 367:P533S

Genes: 2232 367

Variants: G142V L57Q P390L P533S

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 33

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: P390L | Summary: The P390L mutation is associated with a loss of function in the absence of DHT, indicating an alteration in molecular function related to androgen receptor activity. Evidence Type: Functional | Mutation: T575A | Summary: The T575A mutation is linked to a loss of function in the absence of DHT, suggesting it alters the molecular function of the androgen receptor. Evidence Type: Functional | Mutation: R629Q | Summary: The R629Q mutation shows a loss of function in the absence of DHT, indicating a change in the molecular function of the androgen receptor.

Gene→Variant (gene-first): 367:P390L 10499:R629Q 10499:T575A

Genes: 367 10499

Variants: P390L R629Q T575A

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 30

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: D879G | Summary: The D879G mutation is associated with a loss to gain of function, indicating that it alters molecular or biochemical function, with a modest recovery of function at high concentrations of DHT. Evidence Type: Functional | Mutation: Q919R | Summary: The Q919R mutation is described as part of a loss to gain of function, suggesting it alters molecular or biochemical function, although specific details on its activity are not provided. Evidence Type: Functional | Mutation: H874Y | Summary: The H874Y mutation exhibits constitutive activity and displays loss of function relative to wild type (WT) at higher levels of DHT, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: T877A | Summary: The T877A mutation shows a significant constitutive gain of function with a 625% increase in activity compared to WT, indicating a substantial alteration in molecular or biochemical function.

Gene→Variant (gene-first): 10499:D879G 367:H874Y 367:Q919R 367:T877A

Genes: 10499 367

Variants: D879G H874Y Q919R T877A

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 29

Evidence Type(s): Predisposing, Oncogenic, Functional

Summary: Evidence Type: Predisposing | Mutation: K720E | Summary: The K720E mutation is implicated in a 6-fold increased risk of prostate cancer, indicating its role as a predisposing variant. Evidence Type: Oncogenic | Mutation: R726L | Summary: The R726L mutation contributes to tumor development by impairing binding interactions critical for androgen receptor function. Evidence Type: Functional | Mutation: N756 | Summary: The N756 mutation may be involved in AR dimerization, and its mutation to aspartate resulted in complete loss of function. Evidence Type: Functional | Mutation: A765T | Summary: The A765T mutation displayed compromised transactivation activity, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: Y763C | Summary: The Y763C mutation also displayed compromised transactivation activity, suggesting it alters molecular function. Evidence Type: Functional | Mutation: Q902 | Summary: The Q902 residue is part of an H-bonding network, and its mutation to arginine (Q902R) may disrupt this interaction, indicating a functional alteration.

Gene→Variant (gene-first): 367:A765T 9611:K720E 367:N756 367:Q902 367:Q902R 367:R726L 367:Y763C 9611:lysine 720

Genes: 367 9611

Variants: A765T K720E N756 Q902 Q902R R726L Y763C lysine 720

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 28

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: A748V | Summary: The A748V mutation is associated with loss of transactivational activity at physiological levels of DHT, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: A765T | Summary: The A765T mutation is part of a group of loss-of-function mutations that exhibit essentially no transactivational activity at physiological levels of DHT, suggesting a change in molecular function. Evidence Type: Functional | Mutation: L744F | Summary: The L744F mutation is identified as a loss-of-function mutation with no transactivational activity at physiological levels of DHT, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: M749I | Summary: The M749I mutation is classified as a loss-of-function mutation with no transactivational activity at physiological levels of DHT, suggesting a change in molecular function. Evidence Type: Functional | Mutation: N756D | Summary: The N756D mutation is associated with loss of transactivational activity at physiological levels of DHT, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: S759P | Summary: The S759P mutation is part of a group of loss-of-function mutations that exhibit no transactivational activity at physiological levels of DHT, suggesting a change in molecular function. Evidence Type: Functional | Mutation: Y763C | Summary: The Y763C mutation is associated with loss of transactivational activity at physiological levels of DHT, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: K720E | Summary: The K720E mutation is part of a group of mutations showing a distinctive greater loss of function at 1 nM DHT, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: V757A | Summary: The V757A mutation shows a modest loss of function at all levels of DHT, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: V757I | Summary: The V757I mutation is associated with a distinctive greater loss of function at 1 nM DHT, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: Q798E | Summary: The Q798E mutation shows impaired binding to co-regulatory proteins and is associated with a distinctive greater loss of function at 1 nM DHT, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: M886V | Summary: The M886V mutation is part of a group of loss-of-function mutations that exhibit impaired binding to co-regulatory proteins, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: Q902R | Summary: The Q902R mutation is associated with a distinctive greater loss of function at 1 nM DHT, indicating an alteration in molecular function.

Gene→Variant (gene-first): 367:A748V 367:A765T 9611:K720E 367:L744F 1387:M749 1387:M749I 9611:M886V 367:N756D 10514:Q798E 367:Q902R 367:R726L 367:S759P 10514:V757A 10514:V757I 367:Y763C

Genes: 367 9611 1387 10514

Variants: A748V A765T K720E L744F M749 M749I M886V N756D Q798E Q902R R726L S759P V757A V757I Y763C

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 27

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: K910R | Summary: The K910R mutation is associated with driving prostate cancer (PCa) development, despite showing only minor divergence from wild type (WT) and distinctive losses of function. Evidence Type: Functional | Mutation: M886I | Summary: The M886I mutation alters the interaction of the androgen receptor (AR) with co-activators and co-repressors, affecting transactivation ability in prostate cancer.

Gene→Variant (gene-first): 367:K910R 9611:M886 9611:M886I

Genes: 367 9611

Variants: K910R M886 M886I

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 25

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: I672T | Summary: The I672T mutation shows a gain of function at 10 nM DHT and a loss of function at 1 nM, indicating its influence on ligand binding and molecular function. Evidence Type: Functional | Mutation: T575A | Summary: The T575A mutation exhibits a loss of function at low DHT concentrations and a significant gain of function at 10 nM, demonstrating its impact on molecular activity. Evidence Type: Functional | Mutation: R629Q | Summary: The R629Q mutation shows a loss of function at low DHT concentrations and a substantial gain of function at 10 nM, indicating its role in altering molecular function. Evidence Type: Functional | Mutation: A586V | Summary: The A586V mutation transitions from a loss of function at low DHT concentrations to a remarkable gain of function at 10 nM, highlighting its significant effect on transactivational activity. Evidence Type: Functional | Mutation: A587S | Summary: The A587S mutation displays constitutive transactivational activity with modest gains of function across all DHT levels, indicating its influence on molecular function.

Gene→Variant (gene-first): 597:A586V 367:A587S 2908:I672T 10499:R629Q 10499:T575A

Genes: 597 367 2908 10499

Variants: A586V A587S I672T R629Q T575A

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 23

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: P533S | Summary: The P533S mutation functions like wild-type (WT) at low DHT but gains function upon DHT binding, indicating an alteration in molecular function. Evidence Type: Oncogenic | Mutation: G142V | Summary: The G142V mutation shows constitutive activity in the absence of ligand and modest gain of function at all concentrations of DHT, suggesting it contributes to tumor development. Evidence Type: Oncogenic | Mutation: M523V | Summary: The M523V mutation exhibits constitutive activity in the absence of ligand and modest gain of function at all concentrations of DHT, indicating its role in tumor progression. Evidence Type: Oncogenic | Mutation: G524D | Summary: The G524D mutation demonstrates constitutive activity in the absence of ligand and modest gain of function at all concentrations of DHT, suggesting it contributes to tumor development. Evidence Type: Oncogenic | Mutation: M537V | Summary: The M537V mutation shows constitutive activity in the absence of ligand and modest gain of function at all concentrations of DHT, indicating its role in tumor progression.

Gene→Variant (gene-first): 2232:G142V 367:G524D 367:M523V 367:M537V 367:P533S

Genes: 2232 367

Variants: G142V G524D M523V M537V P533S

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 22

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: P269S | Summary: The P269S mutation is associated with wild-type levels of transactivation at 10 nM DHT, indicating it does not alter molecular function in this context. Evidence Type: Functional | Mutation: P390L | Summary: The P390L mutation acquired a 26% gain of function at 10 nM DHT, suggesting it alters molecular function related to AR signaling. Evidence Type: Functional | Mutation: P514S | Summary: The P514S mutation acquired a 30% gain of function at 10 nM DHT, indicating it alters molecular function in the context of AR signaling. Evidence Type: Functional | Mutation: S515G | Summary: The S515G mutation is associated with wild-type levels of transactivation at 10 nM DHT, indicating it does not alter molecular function in this context.

Gene→Variant (gene-first): 367:P269S 367:P390L 367:P514S 10514:S515G

Genes: 367 10514

Variants: P269S P390L P514S S515G

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 21

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: D221H | Summary: The D221H mutation is associated with a loss of function that may contribute to tumor development or progression, as indicated by its context in prostate cancer. Evidence Type: Oncogenic | Mutation: D528G | Summary: The D528G mutation is implicated in tumor development or progression, as suggested by its context in prostate cancer. Evidence Type: Functional | Mutation: S296R | Summary: The S296R mutation alters interaction with the co-repressor N-CoR, leading to reduced transactivational activity, indicating a change in molecular function. Evidence Type: Functional | Mutation: P340L | Summary: The P340L mutation is predicted to create a new alpha-helix and is associated with reduced binding to TFIIF, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: E198G | Summary: The E198G mutation has been shown to maintain transactivational activity similar to wild-type in the presence of ART-27, indicating a functional aspect. Evidence Type: Functional | Mutation: P269S | Summary: The P269S mutation is reported to have transactivational activity comparable to wild-type when stimulated by ART-27, suggesting it alters molecular function. Evidence Type: Functional | Mutation: S334P | Summary: The S334P mutation also maintains transactivational activity similar to wild-type in the presence of ART-27, indicating a functional change. Evidence Type: Oncogenic | Mutation: P340L | Summary: The P340L mutation exemplifies a loss of function that can drive prostate cancer progression through reduced growth suppression, indicating its oncogenic potential.

Gene→Variant (gene-first): 207:D221H 367:D528G 367:E198G 367:P269S 2232:P340L 9611:P504L 367:S296R 367:S334P

Genes: 207 367 2232 9611

Variants: D221H D528G E198G P269S P340L P504L S296R S334P

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 20

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L57Q | Summary: The L57Q mutation is associated with loss of function, indicating an alteration in molecular or biochemical function. Evidence Type: Functional | Mutation: E198G | Summary: The E198G mutation shows a significant reduction in function (50% at 1 nM), indicating an alteration in molecular or biochemical function. Evidence Type: Functional | Mutation: D221H | Summary: The D221H mutation is associated with loss of function, indicating an alteration in molecular or biochemical function. Evidence Type: Functional | Mutation: A234T | Summary: The A234T mutation is located at a critical site affecting function, contributing to loss of transactivational ability. Evidence Type: Functional | Mutation: S296R | Summary: The S296R mutation is associated with loss of function, indicating an alteration in molecular or biochemical function. Evidence Type: Functional | Mutation: S334P | Summary: The S334P mutation is associated with loss of function, indicating an alteration in molecular or biochemical function. Evidence Type: Functional | Mutation: P340L | Summary: The P340L mutation is associated with loss of function and is noted to be present in AIS, indicating an alteration in molecular or biochemical function. Evidence Type: Functional | Mutation: P504L | Summary: The P504L mutation is associated with loss of function, indicating an alteration in molecular or biochemical function. Evidence Type: Functional | Mutation: D528G | Summary: The D528G mutation is associated with loss of function, indicating an alteration in molecular or biochemical function.

Gene→Variant (gene-first): 1387:A234T 207:D221H 367:D528G 367:E198G 367:L57Q 2232:P340L 9611:P504L 367:S296R 367:S334P

Genes: 1387 207 367 2232 9611

Variants: A234T D221H D528G E198G L57Q P340L P504L S296R S334P

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 19

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: G166S | Summary: The mutation G166S showed the least variance from the unmutated receptor, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: M537R | Summary: The mutation M537R exhibited a 23% gain of function at 0.1 nM DHT, suggesting an alteration in molecular function, particularly in a low androgen environment.

Gene→Variant (gene-first): 367:G166S 367:M537R

Genes: 367

Variants: G166S M537R

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: T575 | Summary: The mutation T575 is mentioned in the context of a functionally distinct domain of the androgen receptor, indicating its potential role in altering molecular function. Evidence Type: Functional | Mutation: R629 | Summary: The mutation R629 is highlighted as a highly conserved amino acid, suggesting its importance in the molecular function of the androgen receptor. Evidence Type: Functional | Mutation: I672 | Summary: The mutation I672 is also noted as a highly conserved amino acid, indicating its potential role in the molecular function of the androgen receptor.

Gene→Variant (gene-first): 2908:I672 10499:R629 10499:T575

Genes: 2908 10499

Variants: I672 R629 T575

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: A234 | Summary: The mutation A234 is located within a highly conserved motif, suggesting a possible role in the mechanics of AR function. Evidence Type: Functional | Mutation: D221 | Summary: The mutation D221 is implicated in prostate cancer (PCa) and is present in at least four species, indicating a potential impact on AR function. Evidence Type: Functional | Mutation: E198 | Summary: The mutation E198 is part of a group of amino acids implicated in PCa and is present in multiple species, suggesting its relevance to AR function. Evidence Type: Functional | Mutation: G142 | Summary: The mutation G142 is included in the analysis of amino acids implicated in PCa, indicating its potential role in AR function. Evidence Type: Functional | Mutation: G166 | Summary: The mutation G166 is part of the residues examined for their role in prostate cancer, suggesting its involvement in AR function. Evidence Type: Functional | Mutation: L57 | Summary: The mutation L57 is implicated in prostate cancer and is present in multiple species, indicating its potential role in AR function. Evidence Type: Functional | Mutation: M523 | Summary: The mutation M523 is mentioned as being present in at least four species, suggesting its relevance to the mechanics of AR function. Evidence Type: Functional | Mutation: M537 | Summary: The mutation M537 is included in the analysis of amino acids implicated in PCa, indicating its potential role in AR function. Evidence Type: Functional | Mutation: P269 | Summary: The mutation P269 is located within a highly conserved motif associated with prostate cancer, suggesting its relevance to AR function. Evidence Type: Functional | Mutation: P340 | Summary: The mutation P340 is part of the residues implicated in prostate cancer, indicating its potential role in AR function. Evidence Type: Functional | Mutation: P390 | Summary: The mutation P390 is located within a highly conserved motif, suggesting a possible role in the mechanics of AR function. Evidence Type: Functional | Mutation: P514 | Summary: The mutation P514 is mentioned as being present in at least four species, indicating its relevance to the mechanics of AR function. Evidence Type: Functional | Mutation: P515 | Summary: The mutation P515 is included in the analysis of amino acids implicated in PCa, indicating its potential role in AR function. Evidence Type: Functional | Mutation: G524 | Summary: The mutation G524 is part of the residues examined for their role in prostate cancer, suggesting its involvement in AR function. Evidence Type: Functional | Mutation: S296 | Summary: The mutation S296 is one of the two mutated residues found only in humans, indicating its potential significance in AR function. Evidence Type: Functional | Mutation: S334 | Summary: The mutation S334 is confined to mammals and is implicated in prostate cancer, suggesting its potential role in AR function. Evidence Type: Functional | Mutation: P533 | Summary: The mutation P533 is one of the two residues confined to mammals, indicating its potential significance in AR function.

Gene→Variant (gene-first): 1387:A234 207:D221 367:D528 367:E198 2232:G142 367:G166 367:G524 367:L57 367:M523 367:M537 367:P269 2232:P340 367:P390 367:P514 10514:P515 367:P533 367:S296 367:S334

Genes: 1387 207 367 2232 10514

Variants: A234 D221 D528 E198 G142 G166 G524 L57 M523 M537 P269 P340 P390 P514 P515 P533 S296 S334

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: E152 | Summary: The E152 residue's rotamer configuration is altered in the BCL-2 G101V:S55746 structure, indicating a change in molecular function related to binding affinity. Evidence Type: Functional | Mutation: G101V | Summary: The G101V mutation affects the binding affinity of S55746, demonstrating a change in molecular function due to the variant. Evidence Type: Functional | Mutation: E152A | Summary: The E152A double mutant shows altered binding affinity to S55746, indicating a functional impact on molecular interactions.

Gene→Variant (gene-first): 596:E152 596:E152A 596:G101V 596:V101

Genes: 596

Variants: E152 E152A G101V V101

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Predictive, Oncogenic

Summary: Evidence Type: Functional | Mutation: G101V | Summary: The G101V mutation alters the binding affinity of the BCL-2 protein to the selective antagonist S55746, indicating a change in molecular function compared to the wild-type. Evidence Type: Predictive | Mutation: G101V | Summary: The G101V mutation is associated with a significantly higher LC50 concentration for the drug S55746, suggesting that it may influence the response to this therapy. Evidence Type: Oncogenic | Mutation: G101V | Summary: The G101V mutation in BCL-2 is implicated in altering the drug binding characteristics, which may contribute to tumor development or progression.

Gene→Variant (gene-first): 596:G101V

Genes: 596

Variants: G101V

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: E152 | Summary: The E152 mutation alters the conformation and binding affinity of the BCL-2 protein, impacting its interaction with venetoclax. Evidence Type: Functional | Mutation: E152A | Summary: The E152A mutation maintains comparable binding to wild-type BCL-2 and restores high affinity for venetoclax when combined with G101V. Evidence Type: Functional | Mutation: G101A | Summary: The G101A mutation exhibits a binding affinity to venetoclax that is comparable to wild-type BCL-2, indicating a functional role in drug interaction. Evidence Type: Oncogenic | Mutation: G101V | Summary: The G101V mutation contributes to altered binding dynamics with venetoclax, suggesting a role in tumor development or progression through its impact on drug affinity.

Gene→Variant (gene-first): 596:E152 596:E152A 596:G101A 596:G101V

Genes: 596

Variants: E152 E152A G101A G101V

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: F104L | Summary: The F104L mutation alters the packing environment of the chlorophenyl moiety of the drug, indicating a change in molecular function. Evidence Type: Functional | Mutation: F104 | Summary: The F104 residue plays a role in separating the P2 and P4 pockets of BCL-2, suggesting its importance in molecular function.

Gene→Variant (gene-first): 596:F104 596:F104L 596:L104

Genes: 596

Variants: F104 F104L L104

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: G101V | Summary: The G101V mutation alters drug binding by changing the interactions within the P2 pocket, affecting the positioning of venetoclax in relation to the BCL-2 structure. Evidence Type: Functional | Mutation: G101A | Summary: The G101A mutation introduces a milder bulk at the G101 position, which affects the interactions with venetoclax but maintains the overall positioning of the drug in the P4 pocket. Evidence Type: Functional | Mutation: E152 | Summary: The E152 mutation exhibits a rotamer change that influences the positioning of venetoclax, indicating an alteration in molecular function related to drug binding.

Gene→Variant (gene-first): 596:E152 596:G101 596:G101A 596:G101V

Genes: 596

Variants: E152 G101 G101A G101V

[Paragraph-level] PMCID: PMC3219854 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: Trp557Gly | Summary: The Trp557Gly mutation in KIT is identified as a missense point mutation associated with neurofibromatosis type 1-related gastrointestinal stromal tumors (GISTs), indicating its contribution to tumor development. Evidence Type: Functional | Mutation: Trp557Gly | Summary: The Trp557Gly mutation alters the molecular function of the KIT protein, which is implicated in the pathogenesis of the tumors described.

Gene→Variant (gene-first): 3815:Trp557Gly

Genes: 3815

Variants: Trp557Gly

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L349P | Summary: The L349P mutation is evaluated for its impact on translation and subcellular localization of the ETV6 protein, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: N385fs | Summary: The N385fs mutation is assessed for its effect on translation and subcellular localization of the ETV6 protein, suggesting a change in molecular function. Evidence Type: Functional | Mutation: P214L | Summary: The P214L mutation is described as being detectable in both cytoplasmic and nuclear fractions, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: R369Q | Summary: The R369Q mutation is noted for its presence in both cytoplasmic and nuclear fractions, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: R399C | Summary: The R399C mutation is mentioned as being detectable in both cytoplasmic and nuclear fractions, indicating a potential change in molecular function.

Gene→Variant (gene-first): 2120:L349P 2120:N385fs 2120:P214L 2120:R369Q 2120:R399C

Genes: 2120

Variants: L349P N385fs P214L R369Q R399C

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L349P | Summary: The L349P mutation was assessed for its impact on transcriptional repression by ETV6, showing significantly decreased repression compared to wild-type ETV6. Evidence Type: Functional | Mutation: N385fs | Summary: The N385fs mutation was evaluated for its ability to impair transcriptional repression by ETV6, exhibiting significantly decreased repression relative to wild-type ETV6. Evidence Type: Functional | Mutation: P214L | Summary: The P214L mutation, a germline variant, was compared to other ETV6 mutations and demonstrated significantly decreased transcriptional repression compared to wild-type ETV6. Evidence Type: Functional | Mutation: R369Q | Summary: The R369Q mutation was analyzed alongside other ETV6 variants and showed significantly reduced transcriptional repression compared to wild-type ETV6. Evidence Type: Functional | Mutation: R399C | Summary: The R399C mutation was included in the analysis of ETV6 variants and exhibited significantly decreased transcriptional repression compared to wild-type ETV6.

Gene→Variant (gene-first): 2120:L349P 2120:N385fs 2120:P214L 2120:R369Q 2120:R399C

Genes: 2120

Variants: L349P N385fs P214L R369Q R399C

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L349P | Summary: The L349P mutation is predicted to cause significant conformational changes in the ETV6 protein, suggesting an alteration in its molecular function. Evidence Type: Functional | Mutation: N385fs | Summary: The N385fs mutation is predicted to truncate the ETV6 protein at a region involved in DNA interaction, indicating a change in its biochemical function.

Gene→Variant (gene-first): 2120:L349P 2120:N385fs

Genes: 2120

Variants: L349P N385fs

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Oncogenic, Functional

Summary: Evidence Type: Diagnostic | Mutation: 415 T>C | Summary: The variant 415 T>C is associated with the diagnosis of thrombocytopenia and/or ALL, as it co-segregates with affected individuals in the family. Evidence Type: Oncogenic | Mutation: 415 T>C | Summary: The 415 T>C variant is a somatic mutation that contributes to tumor development, as it is present in all affected family members tested. Evidence Type: Functional | Mutation: L349P | Summary: The L349P mutation results in a substitution that alters the molecular function of the ETV6 protein, impacting its role in cellular processes.

Gene→Variant (gene-first): 10320:415 T>C 2120:L349P 2120:c. T1046C 2120:proline for leucine at codon 349

Genes: 10320 2120

Variants: 415 T>C L349P c. T1046C proline for leucine at codon 349

[Paragraph-level] PMCID: PMC4477877 Section: ABSTRACT PassageIndex: 3

Evidence Type(s): Predisposing, Functional

Summary: Evidence Type: Predisposing | Mutation: L349P | Summary: The L349P mutation is described as a germline mutation associated with inherited susceptibility to acute leukemia, indicating a predisposing factor for the disease. Evidence Type: Predisposing | Mutation: N385fs | Summary: The N385fs mutation is also identified as a germline mutation linked to inherited risk for acute leukemia, supporting its role as a predisposing factor. Evidence Type: Functional | Mutation: L349P | Summary: The L349P mutation alters the localization of the ETV6 protein, preventing it from localizing to the nucleus and affecting its regulatory function. Evidence Type: Functional | Mutation: N385fs | Summary: The N385fs mutation results in an abnormally truncated ETV6 protein, which shows decreased ability to regulate the expression of genes typically suppressed by ETV6, indicating a functional alteration.

Gene→Variant (gene-first): 2120:L349P 2120:N385fs

Genes: 2120

Variants: L349P N385fs

[Paragraph-level] PMCID: PMC4477877 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predisposing, Oncogenic, Functional

Summary: Evidence Type: Predisposing | Mutation: p. L349P | Summary: The p. L349P mutation is identified as a germline variant in a kindred affected by thrombocytopenia and acute lymphoblastic leukemia (ALL), suggesting it confers inherited risk for the disease. Evidence Type: Oncogenic | Mutation: p. N385fs | Summary: The p. N385fs mutation was found in leukemic cells, contributing to tumor development as it is associated with acute lymphoblastic leukemia (ALL) and secondary myelodysplasia/acute myeloid leukemia. Evidence Type: Functional | Mutation: p. N385fs | Summary: The p. N385fs mutation alters the molecular function of ETV6, as it impairs nuclear localization and reduces the ability to regulate the transcription of ETV6 target genes.

Gene→Variant (gene-first): 2120:p. L349P 2120:p. N385fs

Genes: 2120

Variants: p. L349P p. N385fs

[Paragraph-level] PMCID: PMC6547725 Section: RESULTS PassageIndex: 27

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: Gln61 | Summary: The passage discusses the impact of insertions on the catalytic Gln61, indicating that these variants alter molecular function related to GTP hydrolysis. Evidence Type: Oncogenic | Mutation: Gln61 | Summary: The mention of insertions in tumor samples suggests that these variants contribute to tumor development or progression, classifying them as oncogenic.

Gene→Variant (gene-first): 5921:Gln61

Genes: 5921

Variants: Gln61

[Paragraph-level] PMCID: PMC6547725 Section: RESULTS PassageIndex: 25

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: p.G12V | Summary: The HRAS p.G12V variant alters molecular function by inducing phosphorylation of ERK and AKT, indicating its role in RAS signaling pathways. Evidence Type: Oncogenic | Mutation: p.G12V | Summary: The HRAS p.G12V variant contributes to tumor development by enhancing signaling capabilities, as evidenced by increased levels of phosphorylated ERK and AKT in transfected cells.

Gene→Variant (gene-first): 3845:p.G12V

Genes: 3845

Variants: p.G12V

[Paragraph-level] PMCID: PMC6547725 Section: RESULTS PassageIndex: 21

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: p.G12V | Summary: The p.G12V variant of KRAS shows reduced intrinsic GTP hydrolysis rates compared to wild type, indicating an alteration in molecular function. Evidence Type: Oncogenic | Mutation: p.G12V | Summary: The p.G12V variant is classified as a classical oncogenic variant, contributing to tumor development and progression.

Gene→Variant (gene-first): 3845:p.G12V

Genes: 3845

Variants: p.G12V

[Paragraph-level] PMCID: PMC6547725 Section: RESULTS PassageIndex: 18

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: p.G12V | Summary: KRAS p.G12V is described as a classical oncogenic variant, indicating its role in tumor development or progression. The variant's interaction with Raf-RBD and its altered dissociation rate further support its oncogenic properties. Evidence Type: Functional | Mutation: p.G12V | Summary: The variant KRAS p.G12V alters the intrinsic dissociation rate of the nucleotide, demonstrating a change in molecular function compared to wild type KRAS.

Gene→Variant (gene-first): 3845:p.G12V

Genes: 3845

Variants: p.G12V

[Paragraph-level] PMCID: PMC6547725 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: p.Q61L | Summary: The passage discusses the functional consequences of the p.Q61L mutation in relation to RAS signaling, indicating that it is a classic pathogenic missense mutation that may alter molecular function. Evidence Type: Oncogenic | Mutation: p.Q61L | Summary: The p.Q61L mutation is described as a classic pathogenic missense mutation, suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): 4893:p.Q61L

Genes: 4893

Variants: p.Q61L

[Paragraph-level] PMCID: PMC6547725 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: Gln61 | Summary: The residue Gln61 is involved in GTP hydrolysis and is likely affected by insertions that alter molecular interactions, impacting the protein's biochemical function.

Gene→Variant (gene-first): 5921:Gln61

Genes: 5921

Variants: Gln61

[Paragraph-level] PMCID: PMC6547725 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: p.G12A | Summary: The p.G12A mutation is described as affecting a classical position in the P-loop of KRAS, indicating its contribution to tumor development or progression. Evidence Type: Oncogenic | Mutation: p.G13H | Summary: The p.G13H mutation is also noted to affect a classical position in the P-loop of KRAS, suggesting its role in tumor development or progression. Evidence Type: Functional | Mutation: p.Q22K | Summary: The p.Q22K mutation is associated with increased GTP loading, indicating an alteration in molecular or biochemical function.

Gene→Variant (gene-first): 3845:p.G12A 3845:p.G13H 3845:p.Q22K

Genes: 3845

Variants: p.G12A p.G13H p.Q22K

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K131 | Summary: The K131 variant removes a positively charged residue that directly interacts with the negatively charged triphosphate group of ATP, influencing RAD51C function. Evidence Type: Functional | Mutation: R168 | Summary: The R168 variant removes a positively charged residue that directly interacts with the negatively charged triphosphate group of ATP, influencing RAD51C function. Evidence Type: Functional | Mutation: Q133E | Summary: The Q133E variant introduces a negatively charged group that destabilizes the negatively charged triphosphate group of ATP, influencing RAD51C function. Evidence Type: Functional | Mutation: G130R | Summary: The G130R variant introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function. Evidence Type: Functional | Mutation: T132I | Summary: The T132I variant introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function. Evidence Type: Functional | Mutation: T132R | Summary: The T132R variant introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function. Evidence Type: Functional | Mutation: C135Y | Summary: The C135Y variant introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function. Evidence Type: Functional | Mutation: L138F | Summary: The L138F variant introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function. Evidence Type: Functional | Mutation: V140E | Summary: The V140E variant introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function. Evidence Type: Functional | Mutation: R312W | Summary: The R312W variant removes a positively charged residue that may weaken the interaction with the negatively charged gamma phosphate group of ATP, influencing RAD51C activity. Evidence Type: Functional | Mutation: G302V | Summary: The G302V variant disrupts a hydrophobic core and may interfere with RAD51C protomer formation, influencing RAD51C function.

Gene→Variant (gene-first): 5889:16 A 5889:C135Y 5889:E94K 5889:G130R 5889:G302V 5889:K131 5889:L138F 5889:P21S 5889:Q133E 5889:R168 5889:R168G 5889:R312 5889:R312W 5889:T132I 5889:T132R 5892:T86I 5889:V140E 5889:p.Cys135Tyr 5889:p.Thr132Ile 5889:p.Val140Glu

Genes: 5889 5892

Variants: 16 A C135Y E94K G130R G302V K131 L138F P21S Q133E R168 R168G R312 R312W T132I T132R T86I V140E p.Cys135Tyr p.Thr132Ile p.Val140Glu

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: A126T | Summary: The A126T variant is described as a neutral variant that coimmunoprecipitates with RAD51D and XRCC2, indicating it does not alter the molecular function of the RAD51C complexes. Evidence Type: Functional | Mutation: D109Y | Summary: The D109Y variant is also a neutral variant that coimmunoprecipitates with RAD51D and XRCC2, suggesting it does not affect the molecular function of the RAD51C complexes. Evidence Type: Oncogenic | Mutation: L138F | Summary: The L138F variant is identified as a deleterious variant that fails to coimmunoprecipitate with RAD51D and XRCC2, indicating its contribution to tumor development or progression. Evidence Type: Functional | Mutation: L27P | Summary: The L27P variant is classified as a deleterious variant that binds only to XRCC3 and not to RAD51D-XRCC2, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: T336P | Summary: The T336P variant is a deleterious variant that binds only to XRCC3 and not to RAD51D-XRCC2, indicating a change in molecular function. Evidence Type: Functional | Mutation: T86I | Summary: The T86I variant is described as an intermediate variant that binds only to XRCC3 and not to RAD51D-XRCC2, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: D159N | Summary: The D159N variant is classified as an intermediate variant that loses the ability to bind to XRCC3 but retains binding to RAD51D-XRCC2, indicating a change in molecular function. Evidence Type: Functional | Mutation: G162E | Summary: The G162E variant is identified as a deleterious variant that loses the ability to bind to XRCC3 but can still bind to RAD51D-XRCC2, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: S163R | Summary: The S163R variant is classified as a deleterious variant that loses the ability to bind to XRCC3 but retains binding to RAD51D-XRCC2, suggesting a change in molecular function. Evidence Type: Functional | Mutation: G302V | Summary: The G302V variant is identified as a deleterious variant that loses the ability to bind to XRCC3 but can still bind to RAD51D-XRCC2, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: R258H | Summary: The R258H variant, observed as a homozygous variant in a FANCO patient, displays reduced binding for all complex members, indicating a change in molecular function.

Gene→Variant (gene-first): 5889:A126T 5889:D109Y 5889:D159N 5889:G162E 5889:G302V 5889:L138F 5889:L27P 5889:Q133E 5889:R258H 5889:S163R 5889:T336P 5892:T86I 5889:p.Gly162Glu 5889:p.Ser163Arg 5889:p.Thr336Pro 5892:p.Thr86Ile

Genes: 5889 5892

Variants: A126T D109Y D159N G162E G302V L138F L27P Q133E R258H S163R T336P T86I p.Gly162Glu p.Ser163Arg p.Thr336Pro p.Thr86Ile

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: G130R | Summary: The G130R variant alters molecular function by causing a significant decrease in RAD51 foci, indicating a disruption in homologous recombination repair. Evidence Type: Functional | Mutation: K131I | Summary: The K131I variant alters molecular function, leading to a significant decrease in RAD51 foci, which suggests a disruption in homologous recombination repair. Evidence Type: Functional | Mutation: T132R | Summary: The T132R variant affects molecular function, resulting in a significant decrease in RAD51 foci, indicating a disruption in homologous recombination repair. Evidence Type: Functional | Mutation: L138F | Summary: The L138F variant alters molecular function, as evidenced by a decrease in RAD51 foci, suggesting a disruption in homologous recombination repair. Evidence Type: Functional | Mutation: R168G | Summary: The R168G variant impacts molecular function, leading to a significant decrease in RAD51 foci, indicating a disruption in homologous recombination repair.

Gene→Variant (gene-first): 5889:G130R 5889:G302V 5889:K131I 5889:L138F 5889:Q133E 5889:R168G 5889:T132R

Genes: 5889

Variants: G130R G302V K131I L138F Q133E R168G T132R

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional, Predictive

Summary: Evidence Type: Functional | Mutation: L138F | Summary: The L138F variant is characterized as deleterious and shows reduced HDR activity in U2OS cells, indicating that it alters molecular function related to homologous recombination. Evidence Type: Predictive | Mutation: L138F | Summary: The L138F variant is associated with sensitivity to cisplatin and olaparib in CL-V4B cells, suggesting it may correlate with response to specific therapies.

Gene→Variant (gene-first): 5889:L138F

Genes: 5889

Variants: L138F

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional, Predictive

Summary: Evidence Type: Functional | Mutation: G130R | Summary: The G130R variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. Evidence Type: Functional | Mutation: K131I | Summary: The K131I variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. Evidence Type: Functional | Mutation: T132R | Summary: The T132R variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. Evidence Type: Functional | Mutation: Q133E | Summary: The Q133E variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. Evidence Type: Functional | Mutation: L138F | Summary: The L138F variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. Evidence Type: Functional | Mutation: R168G | Summary: The R168G variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. Evidence Type: Functional | Mutation: G302V | Summary: The G302V variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. Evidence Type: Predictive | Mutation: G130R | Summary: The G130R variant showed sensitivity to olaparib compared with WT-complemented cells, indicating a correlation with response to therapy. Evidence Type: Predictive | Mutation: K131I | Summary: The K131I variant showed sensitivity to olaparib compared with WT-complemented cells, indicating a correlation with response to therapy. Evidence Type: Predictive | Mutation: T132R | Summary: The T132R variant showed sensitivity to olaparib compared with WT-complemented cells, indicating a correlation with response to therapy. Evidence Type: Predictive | Mutation: Q133E | Summary: The Q133E variant had intermediate effects on sensitivity to olaparib compared with WT-complemented cells, indicating a correlation with response to therapy. Evidence Type: Predictive | Mutation: G302V | Summary: The G302V variant had intermediate effects on sensitivity to olaparib compared with WT-complemented cells, indicating a correlation with response to therapy.

Gene→Variant (gene-first): 5889:G130R 5889:G302V 5889:K131I 5889:L138F 5889:Q133E 5889:R168G 5889:T132R

Genes: 5889

Variants: G130R G302V K131I L138F Q133E R168G T132R

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: P21S | Summary: The P21S variant induces RAD51 foci formation, indicating it alters molecular function related to DNA damage response. Evidence Type: Functional | Mutation: D109Y | Summary: The D109Y variant induces RAD51 foci formation, indicating it alters molecular function related to DNA damage response. Evidence Type: Functional | Mutation: C147Y | Summary: The C147Y variant induces RAD51 foci formation, indicating it alters molecular function related to DNA damage response. Evidence Type: Functional | Mutation: D108G | Summary: The D108G variant exhibits dramatically reduced RAD51 foci formation, indicating it alters molecular function related to DNA damage response. Evidence Type: Functional | Mutation: C135Y | Summary: The C135Y variant exhibits dramatically reduced RAD51 foci formation, indicating it alters molecular function related to DNA damage response. Evidence Type: Functional | Mutation: V140E | Summary: The V140E variant exhibits dramatically reduced RAD51 foci formation, indicating it alters molecular function related to DNA damage response. Evidence Type: Functional | Mutation: A155E | Summary: The A155E variant exhibits dramatically reduced RAD51 foci formation, indicating it alters molecular function related to DNA damage response. Evidence Type: Functional | Mutation: D159Y | Summary: The D159Y variant exhibits dramatically reduced RAD51 foci formation, indicating it alters molecular function related to DNA damage response. Evidence Type: Functional | Mutation: G306R | Summary: The G306R variant exhibits partially reduced RAD51 foci formation, indicating it alters molecular function related to DNA damage response.

Gene→Variant (gene-first): 5889:A155E 5889:C135Y 5889:C147Y 5888:D108G 5889:D109Y 5889:D159Y 5889:G306R 5889:P21S 5889:V140E 5889:p.Ala155Glu 5888:p.Asp108Gly 5889:p.Asp109Tyr 5889:p.Asp159Tyr 5889:p.Cys147Tyr 5889:p.Gly306Arg 5889:p.Pro21Ser 5889:p.Val140Glu

Genes: 5889 5888

Variants: A155E C135Y C147Y D108G D109Y D159Y G306R P21S V140E p.Ala155Glu p.Asp108Gly p.Asp109Tyr p.Asp159Tyr p.Cys147Tyr p.Gly306Arg p.Pro21Ser p.Val140Glu

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 5

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: E94K | Summary: The variant p.Glu94Lys (E94K) shows a significant reduction in sensitivity to cisplatin and a notable decrease in sensitivity to olaparib, indicating its potential role in predicting treatment response. Evidence Type: Predictive | Mutation: G306R | Summary: The variant p.Gly306Arg (G306R) demonstrates a marked reduction in sensitivity to both cisplatin and olaparib, suggesting its predictive value for treatment response. Evidence Type: Functional | Mutation: E94K | Summary: The variant p.Glu94Lys (E94K) is associated with altered IC50 values for cisplatin and olaparib, indicating a change in molecular function. Evidence Type: Functional | Mutation: G306R | Summary: The variant p.Gly306Arg (G306R) exhibits altered IC50 values for cisplatin and olaparib, suggesting a functional impact on drug response.

Gene→Variant (gene-first): 5889:E94K 5889:G306R 5889:p.Glu94Lys 5889:p.Gly306Arg

Genes: 5889

Variants: E94K G306R p.Glu94Lys p.Gly306Arg

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: A126T | Summary: The A126T mutation was assessed in a cell-based HDR assay, indicating its influence on RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: C135Y | Summary: The C135Y mutation was categorized as deleterious in the HDR assay, demonstrating its impact on RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: D159N | Summary: The D159N mutation was classified as intermediate in the HDR assay, suggesting it alters RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: G125V | Summary: The G125V mutation was identified as deleterious in the HDR assay, indicating its effect on RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: G153D | Summary: The G153D mutation was categorized as deleterious in the HDR assay, reflecting its influence on RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: G264S | Summary: The G264S mutation was classified as neutral in the HDR assay, indicating it does not significantly alter RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: G264V | Summary: The G264V mutation was categorized as neutral in the HDR assay, suggesting it does not impact RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: G3R | Summary: The G3R mutation was reported as neutral in the HDR assay, indicating it does not affect RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: L138F | Summary: The L138F mutation was identified as deleterious in the HDR assay, demonstrating its effect on RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: L219S | Summary: The L219S mutation was classified as neutral in the HDR assay, indicating it does not significantly alter RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: Q143R | Summary: The Q143R mutation was categorized as neutral in the HDR assay, suggesting it does not impact RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: R214C | Summary: The R214C mutation was reported as neutral in the HDR assay, indicating it does not affect RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: R258H | Summary: The R258H mutation was classified as intermediate in the HDR assay, suggesting it alters RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: R312W | Summary: The R312W mutation was identified as deleterious in the HDR assay, demonstrating its effect on RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: R366Q | Summary: The R366Q mutation was reported as neutral in the HDR assay, indicating it does not significantly alter RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: T287A | Summary: The T287A mutation was categorized as neutral in the HDR assay, suggesting it does not impact RAD51C HR DNA repair activity. Evidence Type: Functional | Mutation: V169A | Summary: The V169A mutation was reported as neutral in the HDR assay, indicating it does not affect RAD51C HR DNA repair activity.

Gene→Variant (gene-first): 5889:A126T 5889:C135Y 5889:D159N 5889:G125V 5889:G153D 5889:G264S 5889:G264V 5889:G3R 5889:L138F 5889:L219S 5889:Q143R 5889:R214C 5889:R258H 5889:R312W 5889:R366Q 5889:T287A 5889:V169A 5889:p.Arg214Cys 5889:p.Arg258His 5889:p.Arg312Trp 5889:p.Arg366Gln 5889:p.Asp159Asn 5889:p.Gln143Arg 5889:p.Gly125Val 5889:p.Gly153Asp 5889:p.Gly264Ser 5889:p.Gly264Val 5889:p.Gly3Arg 5889:p.Leu219Ser 5889:p.Thr287Ala 5889:p.Val169Ala

Genes: 5889

Variants: A126T C135Y D159N G125V G153D G264S G264V G3R L138F L219S Q143R R214C R258H R312W R366Q T287A V169A p.Arg214Cys p.Arg258His p.Arg312Trp p.Arg366Gln p.Asp159Asn p.Gln143Arg p.Gly125Val p.Gly153Asp p.Gly264Ser p.Gly264Val p.Gly3Arg p.Leu219Ser p.Thr287Ala p.Val169Ala

[Paragraph-level] PMCID: PMC4868698 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: E483D | Summary: The JAK1E483D mutation is part of a study evaluating the transformation ability of JAK1 mutations, indicating a potential alteration in molecular function. Evidence Type: Oncogenic | Mutation: S703I | Summary: The JAK1S703I mutation is capable of continual proliferation in the absence of IL-3, suggesting it contributes to tumor development or progression. Evidence Type: Oncogenic | Mutation: S729C | Summary: The JAK1S729C mutation serves as a positive control in the study, indicating its role in enabling continual proliferation and suggesting it contributes to tumor development or progression.

Gene→Variant (gene-first): 3716:E483D 3716:S703I 3716:S729C

Genes: 3716

Variants: E483D S703I S729C

[Paragraph-level] PMCID: PMC5029699 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: N540K | Summary: The N540K mutation is reinforced as an important alteration that contributes to tumor development and progression, as it is associated with activating mutations in FGFR3. Evidence Type: Oncogenic | Mutation: K650E | Summary: The K650E mutation is established as a significant alteration that contributes to tumor development and progression, being linked to the activation of FGFR3. Evidence Type: Functional | Mutation: R669G | Summary: The R669G mutation is noted for its role in altering the activation state of FGFR3, although it does not occur at high frequency and may not be linked to activation.

Gene→Variant (gene-first): 2261:K650E 2261:N540K 2261:R669G

Genes: 2261

Variants: K650E N540K R669G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 33

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: V555M | Summary: The variant V555M is associated with the expected efficacy of the inhibitor JNJ42756493, indicating a correlation with response to therapy. Evidence Type: Functional | Mutation: V561M | Summary: The variant V561M is discussed in the context of its interactions within the ATP-binding pocket, suggesting an alteration in molecular function related to drug binding.

Gene→Variant (gene-first): 2261:V555M 2260:V561M

Genes: 2261 2260

Variants: V555M V561M

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 31

Evidence Type(s): Predictive, Functional, Oncogenic

Summary: Evidence Type: Predictive | Mutation: K650E | Summary: The K650E mutation had moderate effects on the efficacy of all inhibitors, indicating a correlation with treatment response. Evidence Type: Predictive | Mutation: N540K | Summary: The N540K substitution affected the efficacy of AZD4547 more significantly, suggesting its role in treatment sensitivity. Evidence Type: Predictive | Mutation: N540S | Summary: The N540S mutation had a pronounced effect on the efficacy of JNJ42756493, indicating its impact on treatment response. Evidence Type: Predictive | Mutation: V555M | Summary: The V555M mutation conferred resistance to AZ12908010 and significantly impacted the efficacy of AZD4547, highlighting its role in treatment resistance. Evidence Type: Functional | Mutation: I538V | Summary: The I538V mutation had a substantial effect on drug binding, indicating an alteration in molecular function. Evidence Type: Oncogenic | Mutation: R669G | Summary: The highly activating R669G mutation contributes to tumor development or progression, supporting its oncogenic potential.

Gene→Variant (gene-first): 2263:I538 2263:I538V 2261:K650E 2261:N540 2261:N540K 2261:N540S 2261:R669G 2261:V555M

Genes: 2263 2261

Variants: I538 I538V K650E N540 N540K N540S R669G V555M

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 30

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: I538V | Summary: The I538V mutation is associated with measurements of Ki values for various FGFR3 inhibitors, indicating its potential role in influencing response to therapy. Evidence Type: Predictive | Mutation: K650E | Summary: The K650E mutation is mentioned in the context of measuring Ki values for FGFR3 inhibitors, suggesting its relevance in therapeutic response. Evidence Type: Predictive | Mutation: N540K | Summary: The N540K mutation is included in the study of Ki values for FGFR3 inhibitors, indicating its potential impact on treatment response. Evidence Type: Predictive | Mutation: N540S | Summary: The N540S mutation is part of the analysis of Ki values for FGFR3 inhibitors, suggesting its relevance in predicting therapeutic outcomes. Evidence Type: Functional | Mutation: V555M | Summary: The V555M mutation is described as a gatekeeper mutation that may alter the molecular function of FGFR3, impacting its interaction with inhibitors. Evidence Type: Functional | Mutation: R669G | Summary: The R669G mutation is noted for its potential allosteric effect, indicating a change in molecular function related to FGFR3. Evidence Type: Functional | Mutation: K650E | Summary: The K650E mutation may have an allosteric effect on FGFR3, suggesting a change in its molecular function. Evidence Type: Functional | Mutation: N540K | Summary: The N540K mutation is mentioned in the context of its location near the ATP binding pocket, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: N540S | Summary: The N540S mutation is also located near the ATP binding pocket, suggesting it may alter the molecular function of FGFR3.

Gene→Variant (gene-first): 2263:I538V 2261:K650E 2261:N540K 2261:N540S 2261:R669G 2261:V555M

Genes: 2263 2261

Variants: I538V K650E N540K N540S R669G V555M

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 27

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: D641 | Summary: The D641 mutation is involved in forming a hydrogen bond with the drug JNJ42756493, indicating that it alters molecular interactions within the FGFR1 protein. Evidence Type: Functional | Mutation: L630 | Summary: The L630 mutation is part of a shallow pocket that interacts with the terminal isopropyl group of JNJ42756493, suggesting it plays a role in the molecular function of the FGFR1 binding site. Evidence Type: Functional | Mutation: V561 | Summary: The V561 mutation is described as the gatekeeper residue that is involved in the binding of JNJ42756493, indicating its role in the molecular function of FGFR1.

Gene→Variant (gene-first): 2260:D641 2260:L630 2260:V561

Genes: 2260

Variants: D641 L630 V561

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 24

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K650E | Summary: The K650E mutation alters the conformation of the A-loop, impacting the allosteric communication within the FGFR2 kinase domain. Evidence Type: Functional | Mutation: R669G | Summary: The R669G mutation is suggested to disrupt inhibitory interactions near the A-loop, contributing to changes in the allosteric mechanism of FGFR1. Evidence Type: Functional | Mutation: R675G | Summary: The R675G mutation is implicated in altering the allosteric mechanism of FGFR1 by affecting the interactions involving the A-loop. Evidence Type: Functional | Mutation: R675 | Summary: The R675 mutation is associated with changes in the allosteric communication within the FGFR1 kinase domain, similar to the R675G variant.

Gene→Variant (gene-first): 2261:K650E 2261:R669G 2260:R675 2260:R675G

Genes: 2261 2260

Variants: K650E R669G R675 R675G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 23

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: R669G | Summary: The R669G mutation in FGFR3 alters molecular interactions and promotes an active conformation, as indicated by significant chemical shift perturbations observed in NMR studies.

Gene→Variant (gene-first): 2261:R669G

Genes: 2261

Variants: R669G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 22

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: R675G | Summary: The R675G mutation alters the molecular interactions within the FGFR1 kinase domain, leading to a change in conformation that affects the overall structure and function of the protein. Evidence Type: Functional | Mutation: R675 | Summary: The R675 residue is involved in critical hydrogen bonding and van der Waals interactions that are essential for maintaining the inactive conformation of FGFR1, indicating its role in molecular function. Evidence Type: Functional | Mutation: H650 | Summary: The H650 residue participates in hydrogen bonding with R675, which is crucial for the structural integrity of the inactive FGFR1 kinase domain, highlighting its functional importance. Evidence Type: Functional | Mutation: Y653 | Summary: The Y653 residue is involved in van der Waals interactions with R675, contributing to the structural stability of the FGFR1 kinase domain and its functional state.

Gene→Variant (gene-first): 2261:H650 2260:R675 2260:R675G 2263:Y653

Genes: 2261 2260 2263

Variants: H650 R675 R675G Y653

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 21

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: R669 | Summary: The R669 mutation in FGFR3 is associated with cancer, indicating its contribution to tumor development or progression. Evidence Type: Functional | Mutation: R to G | Summary: The R to G replacement in FGFR1 KD alters the molecular activity of the protein, suggesting a functional change. Evidence Type: Oncogenic | Mutation: R675G | Summary: The R675G variant in FGFR1 KD shows higher activity compared to wild type, indicating its potential role in tumor development or progression.

Gene→Variant (gene-first): 2260:R to G 2261:R669 2260:R675G

Genes: 2260 2261

Variants: R to G R669 R675G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 20

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: R669G | Summary: The passage discusses the activation mechanism of the FGFR3 R669G mutation, indicating that it alters molecular or biochemical function.

Gene→Variant (gene-first): 2261:R669G

Genes: 2261

Variants: R669G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 19

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: D617G | Summary: The D617G mutation is predicted to reduce protein production or completely inactivate the kinase, indicating a functional alteration. Evidence Type: Functional | Mutation: E466K | Summary: The E466K mutation is predicted to reduce protein production or completely inactivate the kinase, indicating a functional alteration. Evidence Type: Functional | Mutation: G637W | Summary: The G637W mutation is predicted to reduce protein production or completely inactivate the kinase, indicating a functional alteration. Evidence Type: Oncogenic | Mutation: R669 | Summary: The R669 mutation is located within an identified cluster of observed A-loop cancer mutations, suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): 2261:D617G 2263:E466K 2260:G637W 2261:R669

Genes: 2261 2263 2260

Variants: D617G E466K G637W R669

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 18

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: R669G | Summary: The R669G mutation in FGFR3 is associated with altered molecular function, as indicated by enhanced downstream signaling and increased FGFR3 phosphorylation in the NIH3T3 cell line.

Gene→Variant (gene-first): 2261:R669G

Genes: 2261

Variants: R669G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 17

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: G697C | Summary: The G697C mutation does not affect kinase activity directly as measured in vitro, suggesting it may alter FGFR3 function in a cellular setting. Evidence Type: Oncogenic | Mutation: K650E | Summary: The K650E mutation is associated with a transformed phenotype and anchorage independent growth in cell lines, indicating its role in tumor development. Evidence Type: Oncogenic | Mutation: N540K | Summary: The N540K mutation is also linked to a transformed phenotype and anchorage independent growth in cell lines, supporting its contribution to tumor progression.

Gene→Variant (gene-first): 2261:G697C 2261:K650E 2261:N540K

Genes: 2261

Variants: G697C K650E N540K

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: K650E | Summary: The K650E mutation is associated with altered kinase activity, indicating that it affects the molecular function of the FGFR3 protein. Evidence Type: Oncogenic | Mutation: K650E | Summary: The K650E mutation is described as a highly activating variant, suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): 2261:K650E

Genes: 2261

Variants: K650E

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: D617G | Summary: The D617G mutation completely abolished kinase activity, indicating that it alters molecular function. Evidence Type: Functional | Mutation: G637W | Summary: The G637W mutation also resulted in kinase inactivation, demonstrating an alteration in molecular function.

Gene→Variant (gene-first): 2261:D617 2261:D617G 2261:G to W 2260:G637 2260:G637W

Genes: 2261 2260

Variants: D617 D617G G to W G637 G637W

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: G697C | Summary: The G697C mutation is mentioned in the context of FGFR3 KD activity, indicating that it alters molecular or biochemical function. Evidence Type: Oncogenic | Mutation: G697C | Summary: The G697C mutation is described as one of the hotspots, suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): 2261:G697C

Genes: 2261

Variants: G697C

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Predictive

Summary: Evidence Type: Functional | Mutation: D641G | Summary: The D641G mutation resulted in an increase of auto-phosphorylation and substrate phosphorylation, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: D641N | Summary: The D641N mutation also resulted in an increase of auto-phosphorylation and substrate phosphorylation, indicating an alteration in molecular function. Evidence Type: Predictive | Mutation: V555M | Summary: The V555M mutation is described as an acquired resistance mutation to an FGFR inhibitor, indicating a correlation with resistance to a specific therapy. Evidence Type: Functional | Mutation: V555 | Summary: The V555 mutation is associated with an increase in kinase activity, indicating an alteration in molecular function.

Gene→Variant (gene-first): 2260:D641G 2260:D641N 2261:V555 2261:V555M

Genes: 2260 2261

Variants: D641G D641N V555 V555M

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K650E | Summary: The K650E mutation significantly increases auto-phosphorylation of FGFR3 KD, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: K650N | Summary: The K650N mutation results in less activation of FGFR3 KD auto-phosphorylation compared to K650E, suggesting it alters molecular function. Evidence Type: Functional | Mutation: N540K | Summary: The N540K mutation leads to a substantial increase in auto-phosphorylation of FGFR3 KD, indicating a change in molecular function. Evidence Type: Functional | Mutation: N540S | Summary: The N540S mutation is associated with reduced activation of FGFR3 KD auto-phosphorylation, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: R669G | Summary: The R669G mutation is the most activating variant in the assay, resulting in increased auto-phosphorylation of FGFR3 KD, indicating a change in molecular function. Evidence Type: Functional | Mutation: R669Q | Summary: The R669Q mutation also results in increased auto-phosphorylation of FGFR3 KD, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: I538V | Summary: The I538V mutation is the least activating among variants that increase FGFR3 KD auto-phosphorylation, suggesting it alters molecular function.

Gene→Variant (gene-first): 2263:I538V 2261:K650E 2261:K650N 2261:N540K 2261:N540S 2261:R669G 2261:R669Q

Genes: 2263 2261

Variants: I538V K650E K650N N540K N540S R669G R669Q

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K650 | Summary: The mutation FGFR3 K650 has been assessed for its functional impact, indicating that it alters molecular or biochemical function. Evidence Type: Functional | Mutation: N540K | Summary: The mutation FGFR3 N540K has been assessed for its functional impact, indicating that it alters molecular or biochemical function.

Gene→Variant (gene-first): 2261:K650 2261:N540K

Genes: 2261

Variants: K650 N540K

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 7

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: K650 | Summary: The K650 mutation is located in a hot spot within the A-loop of the FGFR3 kinase domain, suggesting its contribution to tumor development or progression. Evidence Type: Oncogenic | Mutation: R669 | Summary: The R669 mutation is situated near the A-loop of the FGFR3 kinase domain, indicating its potential role in tumor development or progression. Evidence Type: Functional | Mutation: N540 | Summary: The N540 mutation is part of the molecular brake in the FGFR3 structure, suggesting it alters molecular or biochemical function. Evidence Type: Functional | Mutation: I538 | Summary: The I538 mutation is also part of the molecular brake in the FGFR3 structure, indicating it may affect molecular or biochemical function.

Gene→Variant (gene-first): 2263:I538 2261:K650 2261:N540 2261:R669

Genes: 2263 2261

Variants: I538 K650 N540 R669

[Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 13

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: c.638_639insA | Summary: The insertion mutation in NF1 leads to a premature stop codon, contributing to tumor development through loss of function and increased activation of the RAS signaling pathway. Evidence Type: Oncogenic | Mutation: c.5101A>T | Summary: The SNV in NF1 results in a premature stop codon, which is associated with tumor progression due to loss of function and enhanced RAS signaling. Evidence Type: Functional | Mutation: c.638_639insA | Summary: This insertion mutation alters the molecular function of NF1 by creating a premature stop codon, leading to loss of function. Evidence Type: Functional | Mutation: c.5101A>T | Summary: The SNV creates a premature stop codon in NF1, affecting its molecular function and resulting in loss of regulatory control over the RAS pathway.

Gene→Variant (gene-first): 4763:c.5101A>T 4763:c.638_639insA 4763:p.Asn214Lys fs*2 4763:p.Lys1701Ter

Genes: 4763

Variants: c.5101A>T c.638_639insA p.Asn214Lys fs*2 p.Lys1701Ter

[Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: c.169A>G; p.Lys57Glu | Summary: The variant c.169A>G in the MAP2K1 gene results in a substitution that alters the molecular function of the MEK1 protein, leading to a gain of function. Evidence Type: Oncogenic | Mutation: c.169A>G; p.Lys57Glu | Summary: The variant c.169A>G is associated with a gain of function in the MEK1 protein, indicating its contribution to tumor development or progression.

Gene→Variant (gene-first): 5604:c.169A>G 5604:p.Lys57Glu

Genes: 5604

Variants: c.169A>G p.Lys57Glu

[Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: c.183A>T; p.Gln61His | Summary: The KRAS variant (c.183A>T; p.Gln61His) was identified in tumor tissue, indicating its potential role in tumor development or progression. Evidence Type: Functional | Mutation: c.183A>T; p.Gln61His | Summary: The variant is associated with molecular alterations, as it was confirmed through ddPCR analysis, suggesting it affects the biochemical function of the KRAS gene.

Gene→Variant (gene-first): 3845:c.183A>T 3845:p.Gln61His

Genes: 3845

Variants: c.183A>T p.Gln61His

[Paragraph-level] PMCID: PMC4695055 Section: RESULTS PassageIndex: 2

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: p.982_1028del47 | Summary: The mutation p.982_1028del47 is associated with the detection of a METex14del transcript, indicating a potential alteration in molecular function related to the MET gene. Evidence Type: Oncogenic | Mutation: p.982_1028del47 | Summary: The presence of the METex14del mutation (p.982_1028del47) suggests a contribution to tumor development or progression, as it is being screened in a cohort of cancer patients.

Gene→Variant (gene-first): 4916:p.982_1028del47

Genes: 4916

Variants: p.982_1028del47

[Paragraph-level] PMCID: PMC3100313 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: R132H | Summary: The IDH1 R132H mutation is identified as a somatic mutation that occurs frequently in gliomas and is implicated in tumorigenesis through its effects on enzyme function and the accumulation of D-2-hydroxyglutarate. Evidence Type: Functional | Mutation: R132H | Summary: The R132H mutation in IDH1 causes a loss of normal enzyme function and a gain-of-function, leading to the reduction of alpha-ketoglutarate to D-2-hydroxyglutarate, which alters the biochemical function of the enzyme.

Gene→Variant (gene-first): 3417:R132H

Genes: 3417

Variants: R132H

[Paragraph-level] PMCID: PMC3100313 Section: RESULTS PassageIndex: 2

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: p.R132H | Summary: The heterozygous mutation p.R132H in IDH1 is associated with glioblastoma, indicating its contribution to tumor development or progression. Evidence Type: Functional | Mutation: p.R132H | Summary: The mutation p.R132H alters the molecular function of the IDH1 enzyme, which is relevant in the context of glioblastoma.

Gene→Variant (gene-first): 728294:R132 79944:arginine to histidine 728294:c.395G>A 3417:p.R132H

Genes: 728294 79944 3417

Variants: R132 arginine to histidine c.395G>A p.R132H

[Paragraph-level] PMCID: PMC2570525 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: AKT1 (E17K) | Summary: The AKT1 E17K mutation is reported as an activating mutation contributing to tumor development in breast, ovarian, and colorectal cancers, as well as melanoma. Evidence Type: Functional | Mutation: AKT3 (E17K) | Summary: The AKT3 E17K mutation results in the activation of AKT when expressed in human melanoma cells, indicating a change in molecular function.

Gene→Variant (gene-first): 207:AKT1 (E17K 207:E17K

Genes: 207

Variants: AKT1 (E17K E17K

[Paragraph-level] PMCID: PMC10161095 Section: ABSTRACT PassageIndex: 3

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: lysine-to-methionine | Summary: The lysine-to-methionine mutation at histone H3 lysine 27 (H3K27M) is associated with the development and progression of diffuse midline gliomas, contributing to the tumor's lethal characteristics. Evidence Type: Functional | Mutation: lysine-to-methionine | Summary: The H3K27M mutation alters histone modifications, impacting the function of the SWI/SNF complex and leading to changes in chromatin accessibility and gene expression.

Gene→Variant (gene-first): 3021:lysine 27 55193:lysine-to-methionine

Genes: 3021 55193

Variants: lysine 27 lysine-to-methionine

[Paragraph-level] PMCID: PMC5111006 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: p.R474C | Summary: The CHEK2 mutation p.R474C alters the tertiary structure of CHK2 by disrupting the salt bridge between p.R474 and p.E394, indicating its functional importance. Evidence Type: Oncogenic | Mutation: p.R474C | Summary: The homozygous CHEK2 variant p.R474C is suggested to be contributory to familial cancer, as inactivation of CHEK2 in mice led to cancers in multiple organs.

Gene→Variant (gene-first): 11200:p.R474 11200:p.R474C

Genes: 11200

Variants: p.R474 p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: p.R474C | Summary: The variant p.R474C alters the molecular function of CHK2, resulting in instability and poor activation by DNA damage compared to wild-type CHK2. Evidence Type: Oncogenic | Mutation: p.R474C | Summary: The variant p.R474C contributes to tumor development or progression by affecting the function of CHK2, a gene implicated in cell cycle regulation and DNA damage response.

Gene→Variant (gene-first): 11200:p.R474C

Genes: 11200

Variants: p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: p.R474C | Summary: The mutation p.R474C in CHK2 is associated with altered molecular function, specifically indicating that the protein is poorly activated in response to DNA damage.

Gene→Variant (gene-first): 11200:p.R474C

Genes: 11200

Variants: p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: p.R210 | Summary: The mutation p.R210 is described in the context of its interaction with the immunoglobulin Fc fragment, but it is noted that it is not well conserved and does not significantly affect the function or structure of the protein. Evidence Type: Functional | Mutation: p.R210Q | Summary: The mutation p.R210Q is mentioned as not likely to affect the function and structure of the protein, indicating a focus on its molecular function.

Gene→Variant (gene-first): 2217:p.R210 2217:p.R210Q

Genes: 2217

Variants: p.R210 p.R210Q

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: p.R474 | Summary: The mutation p.R474 is involved in forming a salt bridge that is crucial for protein stability, indicating its role in altering molecular function. Evidence Type: Functional | Mutation: p.R474C | Summary: The mutation p.R474C disrupts the salt bridge with p.E394, likely leading to protein instability and altering its molecular function.

Gene→Variant (gene-first): 11200:p.R474 11200:p.R474C

Genes: 11200

Variants: p.R474 p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: p.R474 | Summary: The variant p.R474 of CHEK2 was analyzed for its impact on protein function, showing high conservation in homologs, which suggests a potential functional significance. Evidence Type: Functional | Mutation: p.R218 | Summary: The variant p.R218 of FCGRT was assessed for its effect on protein function, with lower conservation in homologs indicating a possible alteration in molecular function.

Gene→Variant (gene-first): 11200:p.R474

Genes: 11200

Variants: p.R474

[Paragraph-level] PMCID: PMC5509015 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: Trp53 deletion | Summary: The deletion of Trp53 in mice contributes to tumor development, as evidenced by the increased incidence and earlier onset of tumors in VhlDelta/DeltaTrp53Delta/DeltaRb1Delta/Delta mice compared to other genotypes. Evidence Type: Functional | Mutation: Trp53 deletion | Summary: The functional deletion of Trp53 alters the molecular behavior of renal epithelial cells, leading to the development of cysts and dysplasia, indicating a change in cellular function associated with tumorigenesis.

Gene→Variant (gene-first): 7428:Trp53 deletion

Genes: 7428

Variants: Trp53 deletion

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Predictive, Oncogenic

Summary: Evidence Type: Functional | Mutation: K-RasG12D | Summary: The K-RasG12D mutation is associated with defective PI3K binding and Akt activation, indicating an alteration in molecular function related to signaling pathways. Evidence Type: Predictive | Mutation: K-RasG12D | Summary: The sensitivity of Ba/F3 cells expressing K-RasG12D to MEK inhibition suggests that this mutation correlates with response to specific therapies, indicating predictive value. Evidence Type: Oncogenic | Mutation: K-RasG12D | Summary: The K-RasG12D mutation contributes to the transformed, cytokine-independent growth of Ba/F3 cells, indicating its role in tumor development.

Gene→Variant (gene-first): 3845:K-RasG12D

Genes: 3845

Variants: K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: A66dup | Summary: The A66dup mutation in K-Ras shows a markedly reduced interaction with FLAG-p110alpha, indicating an alteration in molecular function. Evidence Type: Oncogenic | Mutation: K-RasG12D | Summary: The K-RasG12D mutation is associated with a profound reduction in binding to FLAG-p110alpha, suggesting its role in tumor development or progression. Evidence Type: Functional | Mutation: Y64G | Summary: The Y64G mutation in K-Ras, when combined with K-RasG12D, results in a significantly reduced binding to FLAG-p110alpha, indicating an alteration in molecular function.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D 5290:Y64G

Genes: 5295 3845 5290

Variants: A66dup K-RasG12D Y64G

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: K-RasG12D | Summary: The K-RasG12D mutation alters molecular function, as indicated by the increased levels of pERK and pAkt in response to its expression in Ba/F3 cells. Evidence Type: Oncogenic | Mutation: K-RasG12D | Summary: The K-RasG12D mutation contributes to tumor development or progression, as it is associated with elevated signaling pathways indicative of oncogenic activity.

Gene→Variant (gene-first): 3845:K-RasG12D

Genes: 3845

Variants: K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: K-RasG12D | Summary: The K-RasG12D variant contributes to tumor development by transforming IL-3-dependent Ba/F3 cells to cytokine-independent growth. Evidence Type: Functional | Mutation: K-RasG12D | Summary: The K-RasG12D variant alters molecular function by increasing levels of Ras-GTP in Ba/F3 cells under serum deprivation. Evidence Type: Oncogenic | Mutation: A66dup | Summary: The A66dup variant contributes to tumor development by transforming IL-3-dependent Ba/F3 cells to cytokine-independent growth. Evidence Type: Functional | Mutation: A66dup | Summary: The A66dup variant alters molecular function by increasing levels of Ras-GTP in Ba/F3 cells under serum deprivation.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D

Genes: 5295 3845

Variants: A66dup K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: A66dup | Summary: The A66dup mutation alters the biochemical properties of K-Ras, leading to impaired intrinsic GTPase activity and increased accumulation in the active GTP conformation. Evidence Type: Functional | Mutation: K-RasG12D | Summary: The K-RasG12D mutation exhibits resistance to GAP stimulation and altered GTPase activity, indicating a change in molecular function.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D

Genes: 5295 3845

Variants: A66dup K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: Glutamine 61; Q61 | Summary: The passage discusses potential effects on the molecular function of Glutamine 61 (Q61) due to structural changes from switch 2 insertions, indicating alterations in protein-protein interactions and the GTP conformation of Ras. Evidence Type: Oncogenic | Mutation: Glutamine 61; Q61 | Summary: The analysis suggests that alterations involving Q61 may contribute to tumor development or progression by favoring the GTP conformation of Ras, which is associated with oncogenic activity.

Gene→Variant (gene-first): 3845:Glutamine 61 3845:Q61

Genes: 3845

Variants: Glutamine 61 Q61

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: K-RasG12D | Summary: The K-RasG12D mutation induces cytokine-independent colony formation and contributes to tumor development by promoting hypersensitive growth patterns in hematopoietic progenitor cells. Evidence Type: Functional | Mutation: K-RasG12D | Summary: The K-RasG12D mutation alters the growth response of myeloid progenitors to GM-CSF, indicating a change in molecular function related to colony formation. Evidence Type: Functional | Mutation: A66dup | Summary: The A66dup mutation in K-Ras insertion variants sensitizes myeloid progenitors to GM-CSF, suggesting an alteration in biochemical function related to growth response.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D

Genes: 5295 3845

Variants: A66dup K-RasG12D

[Paragraph-level] PMCID: PMC7785563 Section: RESULTS PassageIndex: 12

Evidence Type(s): Oncogenic, Predisposing, Functional

Summary: Evidence Type: Oncogenic | Mutation: R132H | Summary: The IDH1-R132H mutation is associated with conventional supratentorial IDH-mutant astrocytomas, indicating its role in tumor development or progression. Evidence Type: Predisposing | Mutation: MSH2 (germline) | Summary: The presence of a known deleterious germline MSH2 mutation in cases diagnosed with Lynch syndrome suggests an inherited risk for colorectal cancer. Evidence Type: Predisposing | Mutation: MSH6 (germline) | Summary: The identification of germline mutations in MSH6 in several tumors indicates a hereditary predisposition to MMR-deficiency syndromes, including Lynch syndrome. Evidence Type: Functional | Mutation: MSH6 | Summary: The tumor cell-specific loss of MSH6 expression in one case suggests that the mutation alters the molecular function of the MMR pathway, contributing to tumorigenesis.

Gene→Variant (gene-first): 3417:R132H

Genes: 3417

Variants: R132H

[Paragraph-level] PMCID: PMC10527017 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Predictive, Functional

Summary: Evidence Type: Oncogenic | Mutation: V777L | Summary: The HER2V777L mutation contributes to tumor development and progression in breast cancer, as evidenced by accelerated tumor formation and increased invasion in genetically engineered mice. Evidence Type: Predictive | Mutation: V777L | Summary: The HER2V777L mutation is associated with resistance to the pan-HER tyrosine kinase inhibitor neratinib, indicating its predictive value for therapy response. Evidence Type: Functional | Mutation: V777L | Summary: The HER2V777L mutation alters molecular function, as indicated by changes in gene expression and cell cycle markers in breast cancer organoids.

Gene→Variant (gene-first): 2064:V777L

Genes: 2064

Variants: V777L

[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 18

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: V777L | Summary: The HER2 V777L mutation is associated with altered molecular function as indicated by the changes in phosphorylation levels of various proteins in breast cancer organoids, suggesting a role in signal transduction pathways. Evidence Type: Oncogenic | Mutation: V777L | Summary: The HER2 V777L mutation contributes to tumor development or progression, as evidenced by its presence in the HP mice tumor model and the associated changes in cellular markers related to cancer.

Gene→Variant (gene-first): 2064:V777L

Genes: 2064

Variants: V777L

[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 17

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: V777L | Summary: The HER2V777L mutation is associated with promoting cell proliferation and enhancing the cell cycle process, contributing to tumor development in the context of breast cancer. Evidence Type: Functional | Mutation: V777L | Summary: The HER2V777L mutation alters molecular function by enhancing the phosphorylation of key proteins involved in cell cycle regulation, indicating a role in the signaling pathways that drive cancer progression.

Gene→Variant (gene-first): 2064:V777L

Genes: 2064

Variants: V777L

[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: V777L | Summary: The HER2V777L mutation is implicated in the development of metastatic breast cancer, as evidenced by the observed lung metastasis in transgenic mice expressing this mutation. Evidence Type: Functional | Mutation: V777L | Summary: The HER2V777L mutation alters the invasive phenotype of breast tumor cells, as indicated by the metastatic behavior observed in vitro and in vivo.

Gene→Variant (gene-first): 2064:V777L

Genes: 2064

Variants: V777L

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 23

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: S249C | Summary: The S249C mutation in FGFR3 is associated with altered cell cycle distribution and viability, indicating a change in molecular function related to PLCgamma1 signaling. Evidence Type: Functional | Mutation: Y762F | Summary: The Y762F mutation, when combined with S249C, shows an increase in cell numbers at confluence, suggesting it also alters molecular function in the context of FGFR3 signaling. Evidence Type: Functional | Mutation: K652E | Summary: The K652E mutation is linked to reduced viability and saturation density in TERT-NHUC cells, indicating a functional impact on cell behavior.

Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y762F

Genes: 2261

Variants: K652E S249C Y762F

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 22

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: K652E | Summary: The K652E mutation is associated with a lack of constitutive PLCgamma1 phosphorylation, suggesting it alters molecular function related to PLCgamma1 signaling. Evidence Type: Oncogenic | Mutation: S249C | Summary: The S249C mutation in FGFR3 is linked to morphological transformation, increased proliferation, and colony formation in soft agar, indicating its role in tumor development. Evidence Type: Oncogenic | Mutation: Y762F | Summary: The Y762F mutation, when combined with S249C, contributes to morphological transformation and increased proliferation in NIH-3T3 cells, supporting its oncogenic potential.

Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y762F

Genes: 2261

Variants: K652E S249C Y762F

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 20

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: S249C | Summary: The S249C mutation exhibits complete ligand-independence, failing to stimulate signaling in response to FGF1 treatment. Evidence Type: Functional | Mutation: Y375C | Summary: The Y375C mutation shows a small increase in ERK1/2 activation in response to FGF1 treatment, indicating altered molecular function. Evidence Type: Functional | Mutation: K652E | Summary: The K652E mutation displays increased phosphorylation of PLCgamma1, ERK1/2, and FRS2alpha in response to FGF1 treatment, suggesting a significant alteration in molecular function.

Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 19

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: S249C | Summary: The S249C mutation in FGFR3 exhibits strong constitutive phosphorylation, indicating a change in molecular function that leads to ligand-independence. Evidence Type: Functional | Mutation: Y375C | Summary: The Y375C mutation in FGFR3 shows increased levels of phosphorylation in response to ligand stimulation, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: K652E | Summary: The K652E mutation in FGFR3 also demonstrates increased phosphorylation levels in response to ligand stimulation, indicating a change in molecular function.

Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: S249C | Summary: The S249C mutation in FGFR3 was associated with increased phosphorylation of PLCgamma1, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: Y375C | Summary: The Y375C mutation in FGFR3 was linked to increased phosphorylation of PLCgamma1, suggesting a change in biochemical function.

Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K652E | Summary: The K652E mutation in FGFR3 alters the phosphorylation levels and activation state of the receptor, indicating a change in molecular function. Evidence Type: Functional | Mutation: S249C | Summary: The S249C mutation in FGFR3 leads to ligand-independent dimerization, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: Y375C | Summary: The Y375C mutation in FGFR3 also results in ligand-independent dimerization, indicating a change in molecular function.

Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: K652E | Summary: The K652E mutation in FGFR3 is associated with altered molecular function, as indicated by the differential expression of regulators of cell survival affecting cell viability. Evidence Type: Oncogenic | Mutation: K652E | Summary: The K652E mutation in FGFR3 contributes to tumor development or progression, as suggested by its impact on cell viability in the context of mutant FGFR3 expression.

Gene→Variant (gene-first): 2261:K652E

Genes: 2261

Variants: K652E

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: S249C | Summary: The S249C mutation in FGFR3 alters the expression and phosphorylation of the retinoblastoma protein (RB) and increases CDK1 levels, indicating a change in molecular function related to cell cycle regulation. Evidence Type: Functional | Mutation: Y375C | Summary: The Y375C mutation in FGFR3 is associated with altered expression and phosphorylation of the retinoblastoma protein (RB) and increased CDK1 levels, suggesting a functional impact on cell cycle-related proteins. Evidence Type: Functional | Mutation: K652E | Summary: The K652E mutation in FGFR3 results in a distinct protein profile with low RB and intermediate CDK1 levels, indicating a change in molecular function compared to other mutants.

Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: S249C | Summary: The S249C mutation in FGFR3 is associated with increased cell viability at confluence compared to controls, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: Y375C | Summary: The Y375C mutation in FGFR3 also shows increased cell viability at confluence, suggesting it alters molecular or biochemical function.

Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: S249C | Summary: The S249C mutation alters the cell cycle profile, with a lower percentage of cells in the G0/G1 phase compared to control cells, indicating a change in molecular function. Evidence Type: Functional | Mutation: Y375C | Summary: The Y375C mutation exhibits a cell cycle profile that is intermediate between S249C mutants and control cells, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: K652E | Summary: The K652E mutation shows a cell cycle profile that is also intermediate between S249C mutants and control cells, indicating a change in molecular function.

Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K652E | Summary: The K652E mutation in FGFR3 does not significantly alter the saturation density of cells compared to controls, indicating a lack of a strong phenotypic effect. Evidence Type: Functional | Mutation: S249C | Summary: The S249C mutation shows a greater phenotypic effect compared to K652E and wildtype FGFR3, suggesting it alters molecular or biochemical function. Evidence Type: Functional | Mutation: Y375C | Summary: The Y375C mutation is associated with a phenotypic effect that is less than S249C but greater than K652E, indicating it also alters molecular or biochemical function.

Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: S249C | Summary: The S249C mutation in FGFR3 alters the molecular behavior of urothelial cells, leading to increased saturation density and changes in cell morphology. Evidence Type: Functional | Mutation: Y375C | Summary: The Y375C mutation in FGFR3 results in increased saturation density and morphological changes in urothelial cells, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: K652E | Summary: The K652E mutation in FGFR3 is associated with changes in cell morphology and behavior, suggesting an alteration in molecular function, although specific effects were not detailed in the passage.

Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K652E | Summary: The K652E mutation alters molecular function by resulting in high levels of constitutive receptor phosphorylation and activating downstream signaling pathways. Evidence Type: Functional | Mutation: S249C | Summary: The S249C mutation alters molecular function by leading to receptor activation and increased phosphorylation of downstream signaling proteins. Evidence Type: Functional | Mutation: Y375C | Summary: The Y375C mutation alters molecular function by causing receptor activation and increased phosphorylation of downstream signaling proteins.

Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 24

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: R625C | Summary: The SF3B1 R625C mutation is associated with clonal evolution in patients with MDS-EB, indicating its contribution to tumor development. Evidence Type: Oncogenic | Mutation: K700E | Summary: The SF3B1 K700E mutation was acquired during the transformation to AML, suggesting its role in tumor progression. Evidence Type: Functional | Mutation: E862K | Summary: The SETBP1 E862K mutation is mentioned in the context of transformation, indicating a potential alteration in molecular function related to disease evolution.

Gene→Variant (gene-first): 26040:E862K 23451:K700E 23451:R625C

Genes: 26040 23451

Variants: E862K K700E R625C

[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: K700E | Summary: The SF3B1 K700E mutation is associated with distinct alternative splicing events and altered molecular functions in myelodysplastic syndromes (MDS), indicating its role in splicing and mRNA processing. Evidence Type: Oncogenic | Mutation: K700E | Summary: The SF3B1 K700E mutation contributes to tumor development and progression in myelodysplastic syndromes (MDS) by influencing the frequency and type of alternative splicing events.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K700E | Summary: The passage suggests that splicing analysis is being conducted to compare the K700E mutation with non-K700E mutated MDS, indicating that the K700E variant may alter molecular or biochemical function related to splicing.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC3542862 Section: RESULTS PassageIndex: 7

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: H1047R | Summary: The H1047R mutation in PIK3CA is associated with increased intracellular AKT phosphorylation, contributing to tumor development and progression. Evidence Type: Functional | Mutation: p.Glu542 | Summary: The p.Glu542 mutation in PIK3CA alters molecular function by increasing intracellular AKT phosphorylation, promoting cell survival and proliferation. Evidence Type: Oncogenic | Mutation: p.His1047 | Summary: The p.His1047 mutation in PIK3CA is linked to increased AKT phosphorylation, which is implicated in tumor development and progression.

Gene→Variant (gene-first): 5290:H1047R 5290:p.Glu542 5290:p.His1047

Genes: 5290

Variants: H1047R p.Glu542 p.His1047

[Paragraph-level] PMCID: PMC2837563 Section: ABSTRACT PassageIndex: 6

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: Ala146Thr | Summary: The Ala146Thr mutation is associated with phenotypes similar to hotspot mutations, indicating its contribution to tumor development or progression. Evidence Type: Oncogenic | Mutation: Lys117Asn | Summary: The Lys117Asn mutation exhibits phenotypes similar to hotspot mutations, suggesting its role in tumor development or progression. Evidence Type: Functional | Mutation: Leu19Phe | Summary: The Leu19Phe mutation is described as having an attenuated phenotype, indicating a potential alteration in molecular or biochemical function. Evidence Type: Oncogenic | Mutation: Arg164Gln | Summary: The Arg164Gln mutation is phenotypically equivalent to wild-type K-Ras, but its presence in tumors suggests a potential role in tumor development or progression.

Gene→Variant (gene-first): 3845:Ala146Thr 3845:Arg164Gln 3845:Leu19Phe 3845:Lys117Asn

Genes: 3845

Variants: Ala146Thr Arg164Gln Leu19Phe Lys117Asn

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: R164Q | Summary: The R164Q mutation showed relatively few changes in gene expression or reduced pathway activation compared to other mutants, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: A146T | Summary: The A146T mutation influenced gene expression similarly to other activating mutations, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: K117N | Summary: The K117N mutation clustered with other mutants and influenced gene expression, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: L19F | Summary: The L19F mutation influenced gene expression, albeit to a lesser extent than the other activating mutations, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: G13D | Summary: The G13D mutation is described as an activating mutation that influences gene expression, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: Q61H | Summary: The Q61H mutation is characterized as an activating mutation that influences gene expression, indicating an alteration in molecular function.

Gene→Variant (gene-first): 3845:A146T 3845:G13D 3845:K117N 3845:L19F 3845:Q61H 3845:R164Q

Genes: 3845

Variants: A146T G13D K117N L19F Q61H R164Q

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: A146T | Summary: The A146T mutation is associated with distinct phenotypic characteristics as indicated by transcription-profiling experiments, suggesting it alters molecular function. Evidence Type: Functional | Mutation: G12C | Summary: The G12C mutation is part of a gene cluster that shows similarity to wild-type K-Ras, indicating it may alter molecular function. Evidence Type: Functional | Mutation: G12D | Summary: The G12D mutation is included in a gene cluster that suggests it alters molecular function, as evidenced by transcription-profiling experiments. Evidence Type: Functional | Mutation: G12V | Summary: The G12V mutation is part of a gene cluster that indicates it alters molecular function, as shown by transcription-profiling experiments. Evidence Type: Functional | Mutation: G13D | Summary: The G13D mutation is associated with distinct phenotypic characteristics, suggesting it alters molecular function based on clustering analysis. Evidence Type: Functional | Mutation: K117N | Summary: The K117N mutation clusters with activating mutations, indicating it alters molecular function as suggested by transcription-profiling data. Evidence Type: Functional | Mutation: L19F | Summary: The L19F mutation is part of a subcluster that suggests it alters molecular function, consistent with Ras GTPase assay data. Evidence Type: Functional | Mutation: R164Q | Summary: The R164Q mutation, while initially surprising in its clustering, suggests an 'activating' phenotype, indicating it alters molecular function.

Gene→Variant (gene-first): 3845:A146T 3845:G12C 3845:G12D 3845:G12V 3845:G13D 3845:K117N 3845:L19F 3845:R164Q

Genes: 3845

Variants: A146T G12C G12D G12V G13D K117N L19F R164Q

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: A146T | Summary: The A146T mutation is shown to be in the active GTP-bound conformation, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: G12V | Summary: The G12V mutation is identified as being in the active GTP-bound conformation, suggesting a change in molecular function. Evidence Type: Functional | Mutation: K117N | Summary: The K117N mutation is confirmed to be in the active GTP-bound conformation, reflecting an alteration in molecular function. Evidence Type: Functional | Mutation: L19F | Summary: The L19F mutation is demonstrated to be in the active GTP-bound conformation, indicating a change in molecular function.

Gene→Variant (gene-first): 3845:A146T 3845:G12V 3845:K117N 3845:L19F 3845:R164Q

Genes: 3845

Variants: A146T G12V K117N L19F R164Q

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 20

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: G12 | Summary: The G12 variant is associated with alterations in molecular function, particularly in relation to GAP-mediated hydrolysis and GTP-binding domain activity. Evidence Type: Functional | Mutation: G13 | Summary: The G13 variant exhibits changes in biochemical properties that affect RAF affinity and may influence downstream signaling mechanisms. Evidence Type: Functional | Mutation: Q61 | Summary: The Q61 variant is implicated in functional differences related to GTP hydrolysis and signaling pathways, as indicated by its interaction with RAS proteins.

Gene→Variant (gene-first): 3845:G12 3845:G13 3845:Q61

Genes: 3845

Variants: G12 G13 Q61

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 19

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: G12 | Summary: The G12 mutation is associated with distinct vulnerabilities to the enzyme, indicating that it alters molecular or biochemical function. Evidence Type: Functional | Mutation: G12C | Summary: The G12C mutation conveys a different level of downstream activity, suggesting it alters molecular or biochemical function. Evidence Type: Functional | Mutation: G12D | Summary: The G12D mutation has been shown to have a specific level of downstream activity, indicating an alteration in molecular or biochemical function. Evidence Type: Functional | Mutation: G13 | Summary: The G13 mutation exhibits higher induction with higher variance, suggesting it alters molecular or biochemical function. Evidence Type: Functional | Mutation: Q61 | Summary: The Q61 mutation is part of the broader distribution of KRAS hotspot variants, indicating it alters molecular or biochemical function.

Gene→Variant (gene-first): 3845:G12 3845:G12C 3845:G12C/D 3845:G12D 3845:G13 3845:Q61

Genes: 3845

Variants: G12 G12C G12C/D G12D G13 Q61

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: G12S | Summary: G12S is predicted to have a decreased RAF affinity, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: G13V | Summary: G13V is predicted to have an intermediate decrease in RAF affinity, suggesting a change in molecular function. Evidence Type: Functional | Mutation: Q61P | Summary: Q61P is predicted to have an intermediate decrease in RAF affinity, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: A59T | Summary: A59T is predicted to have an intermediate decrease in RAF affinity, suggesting a change in molecular function. Evidence Type: Functional | Mutation: A146V | Summary: A146V is predicted to have an intermediate decrease in RAF affinity, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: Q61H | Summary: Q61H shows relatively smaller changes in RAF affinity, suggesting a minor alteration in molecular function. Evidence Type: Functional | Mutation: A18D | Summary: A18D shows relatively smaller changes in RAF affinity, indicating a minor alteration in molecular function. Evidence Type: Functional | Mutation: Q22K | Summary: Q22K shows relatively smaller changes in RAF affinity, suggesting a minor alteration in molecular function. Evidence Type: Functional | Mutation: G13C | Summary: G13C is predicted to have RAF affinity comparable to WT, indicating no significant alteration in molecular function. Evidence Type: Functional | Mutation: G13S | Summary: G13S is predicted to have RAF affinity comparable to WT, indicating no significant alteration in molecular function. Evidence Type: Functional | Mutation: Q61R | Summary: Q61R is predicted to have RAF affinity comparable to WT, indicating no significant alteration in molecular function. Evidence Type: Functional | Mutation: L19F | Summary: L19F is predicted to have RAF affinity comparable to WT, indicating no significant alteration in molecular function. Evidence Type: Functional | Mutation: T74P | Summary: T74P is predicted to have RAF affinity comparable to WT, indicating no significant alteration in molecular function. Evidence Type: Functional | Mutation: K117N | Summary: K117N is predicted to have RAF affinity comparable to WT, indicating no significant alteration in molecular function. Evidence Type: Functional | Mutation: R164Q | Summary: R164Q is predicted to have RAF affinity comparable to WT, indicating no significant alteration in molecular function.

Gene→Variant (gene-first): 3265:A146V 673:A18D 3265:A59T 3845:G12 3845:G12S 3845:G13C 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H 3845:Q61P 4893:Q61R 3845:R164Q 22882:T74P

Genes: 3265 673 3845 4893 22882

Variants: A146V A18D A59T G12 G12S G13C G13V K117N L19F Q22K Q61H Q61P Q61R R164Q T74P

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: T74P | Summary: The T74P variant alters RAF affinity, indicating a change in molecular function related to tumor development. Evidence Type: Functional | Mutation: R164Q | Summary: The R164Q variant resembles hotspot variants in terms of RAF affinity, suggesting it alters molecular function. Evidence Type: Functional | Mutation: L19F | Summary: The L19F variant shows a pattern of RAF affinity similar to other variants, indicating a change in molecular function. Evidence Type: Functional | Mutation: K117N | Summary: The K117N variant's RAF affinity profile suggests it alters molecular function in a manner similar to other variants. Evidence Type: Functional | Mutation: A18D | Summary: The A18D variant resembles other variants in RAF affinity, indicating a change in molecular function. Evidence Type: Functional | Mutation: Q22K | Summary: The Q22K variant shows a similar RAF affinity profile to other variants, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: A146T | Summary: The A146T variant's RAF affinity profile indicates a change in molecular function related to tumor development. Evidence Type: Functional | Mutation: G12R | Summary: The G12R variant clusters with other variants in terms of RAF affinity, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: A59T | Summary: The A59T variant's clustering with other variants indicates a change in molecular function related to RAF affinity. Evidence Type: Functional | Mutation: A146V | Summary: The A146V variant's RAF affinity profile suggests it alters molecular function in a manner similar to other variants. Evidence Type: Functional | Mutation: G12C | Summary: The G12C variant shows a distinct RAF affinity profile, indicating a change in molecular function. Evidence Type: Functional | Mutation: G12C/D | Summary: The G12C/D variant's RAF affinity profile suggests an alteration in molecular function. Evidence Type: Functional | Mutation: G12V | Summary: The G12V variant's RAF affinity profile indicates a change in molecular function. Evidence Type: Functional | Mutation: G12S | Summary: The G12S variant shows a distinct RAF affinity profile, indicating a change in molecular function. Evidence Type: Functional | Mutation: Q61H | Summary: The Q61H variant's RAF affinity profile suggests it alters molecular function. Evidence Type: Functional | Mutation: Q61L | Summary: The Q61L variant shows a similar RAF affinity profile to other variants, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: Q61P | Summary: The Q61P variant's RAF affinity profile indicates a change in molecular function. Evidence Type: Functional | Mutation: Q61R | Summary: The Q61R variant shows a distinct RAF affinity profile, indicating a change in molecular function. Evidence Type: Functional | Mutation: G13C | Summary: The G13C variant's RAF affinity profile suggests it alters molecular function. Evidence Type: Functional | Mutation: G13D | Summary: The G13D variant shows a similar RAF affinity profile to other variants, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: G13V | Summary: The G13V variant's RAF affinity profile indicates a change in molecular function. Evidence Type: Functional | Mutation: G13S | Summary: The G13S variant shows a distinct RAF affinity profile, indicating a change in molecular function.

Gene→Variant (gene-first): 3845:A146T 3265:A146V 673:A18D 3265:A59T 3845:G12C 3845:G12C/D 3845:G12R 3845:G13C/D 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H/L 3845:Q61P 4893:Q61R 3845:R164Q 22882:T74P 22882:V/A

Genes: 3845 3265 673 4893 22882

Variants: A146T A146V A18D A59T G12C G12C/D G12R G13C/D G13V K117N L19F Q22K Q61H/L Q61P Q61R R164Q T74P V/A

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: A146T | Summary: A146T is suggested to alter molecular function by modulating GAP binding and changing the probability of locally unfolded conformations, impacting GAP-mediated hydrolysis rates. Evidence Type: Functional | Mutation: A146V | Summary: A146V is indicated to affect molecular function, as it associates with higher relative GAP-mediated hydrolysis compared to A146T. Evidence Type: Functional | Mutation: A59T | Summary: A59T is mentioned in the context of comparing its effects to G13D and Q61H, suggesting it may alter molecular function related to GAP-mediated hydrolysis. Evidence Type: Functional | Mutation: K117N | Summary: K117N is noted to have comparable effects to G13D and Q61H, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: G12A/R | Summary: G12A/R is associated with comparable effects to G12S and is implicated in altering molecular function related to GAP-mediated hydrolysis. Evidence Type: Functional | Mutation: G12D | Summary: G12D is discussed in the context of conflicting reports regarding its effects, suggesting it may alter molecular function. Evidence Type: Functional | Mutation: G12S | Summary: G12S is indicated to have comparable effects to G12A/R and is involved in altering molecular function related to GAP-mediated hydrolysis. Evidence Type: Functional | Mutation: G13C | Summary: G13C is suggested to have a relatively lower effect compared to G13V, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: G13D | Summary: G13D is mentioned in the context of its effects on GAP-mediated hydrolysis, suggesting it may alter molecular function. Evidence Type: Functional | Mutation: G13V | Summary: G13V is indicated to have a significant effect on GAP-mediated hydrolysis, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: L19F | Summary: L19F is compared to G13D and Q61H, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: Q61H | Summary: Q61H is mentioned in relation to its effects on GAP-mediated hydrolysis, suggesting it may alter molecular function.

Gene→Variant (gene-first): 3845:A146T 3265:A146V 673:A18D 3265:A59T 3845:G12A/R 3845:G12D 3845:G12S 3845:G13C 3845:G13D 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H 22882:T74P

Genes: 3845 3265 673 22882

Variants: A146T A146V A18D A59T G12A/R G12D G12S G13C G13D G13V K117N L19F Q22K Q61H T74P

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: A146V | Summary: The A146V mutation is associated with alterations in local stability and may modulate local unfolding, indicating a change in molecular function. Evidence Type: Functional | Mutation: G13C | Summary: The G13C mutation is part of a group of variants that relate to local stability and may affect local unfolding, suggesting a functional impact. Evidence Type: Functional | Mutation: G13V | Summary: The G13V mutation is included in a cluster of variants that influence local stability and local unfolding probabilities, indicating a functional alteration. Evidence Type: Functional | Mutation: K117N | Summary: The K117N mutation is identified as a non-hotspot variant that may affect local stability and local unfolding, suggesting a change in molecular function.

Gene→Variant (gene-first): 3265:A146V 3845:G13C 3265:G13V 3845:K117N

Genes: 3265 3845

Variants: A146V G13C G13V K117N

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: A146T | Summary: The variant A146T is associated with increased GTP binding, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: A146T/V | Summary: The variant A146T/V shows differences in behavior compared to hotspot variants, suggesting a functional impact on molecular activity. Evidence Type: Functional | Mutation: A59T | Summary: The variant A59T has a distinct profile among the mutants, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: G12A/R | Summary: The G12A/R variant is part of a cluster that shows similarities with other variants, suggesting functional implications. Evidence Type: Functional | Mutation: G12A/R/S | Summary: The G12A/R/S variant is included in a cluster with other variants, indicating potential functional relevance. Evidence Type: Functional | Mutation: G12V/D | Summary: The G12V/D variant is associated with increased GTP binding, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: G13C | Summary: The G13C variant is part of a cluster that indicates functional similarities with other variants. Evidence Type: Functional | Mutation: G13V/D | Summary: The G13V/D variant is included in a cluster that suggests functional implications. Evidence Type: Functional | Mutation: K177N | Summary: The K177N variant is associated with increased GTP binding, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: L19F | Summary: The L19F variant shows similarities with hotspot variants, suggesting functional relevance. Evidence Type: Functional | Mutation: Q22K | Summary: The Q22K variant is associated with increased GTP binding, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: Q61 | Summary: The Q61 variant is part of a cluster that indicates functional implications. Evidence Type: Functional | Mutation: Q61H | Summary: The Q61H variant is associated with increased GTP binding, suggesting a potential alteration in molecular function. Evidence Type: Functional | Mutation: Q61L/P | Summary: The Q61L/P variant is included in a cluster that suggests functional implications. Evidence Type: Functional | Mutation: R164Q | Summary: The R164Q variant behaves like wild-type KRAS, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: T74P | Summary: The T74P variant shows similarities with hotspot variants, suggesting functional relevance.

Gene→Variant (gene-first): 3845:A146T 3845:A146T/V 3265:A59T 3845:G12A/R 3845:G12A/R/S 3845:G12V/D 3845:G13C 3845:G13V/D 673:K177N 3845:L19F 3845:Q22K 3845:Q61 3845:Q61H 3845:Q61L/P 3845:R164Q 22882:T74P

Genes: 3845 3265 673 22882

Variants: A146T A146T/V A59T G12A/R G12A/R/S G12V/D G13C G13V/D K177N L19F Q22K Q61 Q61H Q61L/P R164Q T74P

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: G12 | Summary: The G12 mutation is associated with alterations in the biochemical properties of the GTPase encoded by KRAS, affecting functions such as GTP binding and nucleotide exchange. Evidence Type: Functional | Mutation: G13 | Summary: The G13 mutation is linked to changes in the biochemical properties of the KRAS GTPase, influencing aspects like GTP binding and nucleotide exchange. Evidence Type: Functional | Mutation: Q61 | Summary: The Q61 mutation affects the biochemical properties of the KRAS GTPase, impacting functions such as GTP binding and nucleotide exchange. Evidence Type: Functional | Mutation: T74 | Summary: The T74 mutation is associated with alterations in the biochemical properties of the KRAS GTPase, influencing functions like GTP binding and nucleotide exchange. Evidence Type: Functional | Mutation: G12V | Summary: The G12V mutation is specifically noted for having all six biochemical measurements, indicating its significant impact on the functional properties of the KRAS GTPase.

Gene→Variant (gene-first): 3845:G12 3845:G12V 3845:G13 3845:Q61 22882:T74

Genes: 3845 22882

Variants: G12 G12V G13 Q61 T74

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 18

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: C797 | Summary: The mutation C797 is involved in forming a covalent bond with an inhibitor, indicating that it alters molecular or biochemical function. Evidence Type: Functional | Mutation: T790 | Summary: The mutation T790 is described in the context of its interaction with a quinoline substituent, suggesting it alters molecular or biochemical function.

Gene→Variant (gene-first): 1956:C797 1956:T790

Genes: 1956

Variants: C797 T790

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: C797 | Summary: The C797 mutation forms a covalent bond with the inhibitor, indicating an alteration in molecular function related to drug binding. Evidence Type: Oncogenic | Mutation: T790M | Summary: The T790M mutation is associated with an inactive kinase conformation, contributing to tumor development or progression. Evidence Type: Oncogenic | Mutation: V948R | Summary: The V948R mutation prevents the formation of the activating asymmetric dimer interaction, indicating its role in tumor development or progression.

Gene→Variant (gene-first): 1956:C797 1956:T790M 1956:V948R

Genes: 1956

Variants: C797 T790M V948R

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: T790M | Summary: The T790M mutation is associated with altered molecular or biochemical function as it is studied in the context of cocrystal structures with various inhibitors. Evidence Type: Functional | Mutation: V948R | Summary: The V948R mutation is associated with altered molecular or biochemical function as it is studied in the context of cocrystal structures with various inhibitors.

Gene→Variant (gene-first): 1956:T790M 1956:V948R

Genes: 1956

Variants: T790M V948R

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L858R | Summary: The L858R mutation alters the enzyme kinetic parameters of EGFR, demonstrating a significant increase in catalytic efficiency compared to wild-type EGFR. Evidence Type: Functional | Mutation: T790M | Summary: The T790M mutation is associated with altered enzyme kinetics, showing increased catalytic rates compared to wild-type EGFR. Evidence Type: Functional | Mutation: Glu4 | Summary: The Glu4 mutation is evaluated in terms of its impact on enzyme kinetics, indicating a functional alteration in comparison to wild-type EGFR.

Gene→Variant (gene-first): 7294:Glu4 1956:L858R 1956:T790M

Genes: 7294 1956

Variants: Glu4 L858R T790M

[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: S310F | Summary: The S310F HER2 variant alters the interaction efficiency with EGFR, as indicated by the fluorescence intensity measurements in the cell lysates, suggesting a change in molecular function.

Gene→Variant (gene-first): 2064:S310F

Genes: 2064

Variants: S310F

[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: S310F | Summary: The S310F HER2 mutant was analyzed for its ability to form a heterodimer with EGFR, indicating that it alters molecular interactions and functions in a cellular context. Evidence Type: Oncogenic | Mutation: S310F | Summary: The S310F HER2 mutation is implicated in altered reactivity to therapeutic antibodies, suggesting a role in tumor development or progression.

Gene→Variant (gene-first): 2064:S310F

Genes: 2064

Variants: S310F

[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: S310F | Summary: The S310F HER2 mutant alters molecular interactions by forming heterodimers with the EGFR, indicating a change in biochemical function.

Gene→Variant (gene-first): 2064:S310F

Genes: 2064

Variants: S310F

[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: S310F | Summary: The S310F HER2 mutant was confirmed to be expressed in 5637 cells through immunoprecipitation experiments, indicating that the variant alters the molecular function of HER2. Evidence Type: Oncogenic | Mutation: S310F | Summary: The expression of the S310F HER2 mutant in 5637 cells suggests that this somatic variant may contribute to tumor development or progression.

Gene→Variant (gene-first): 2064:S310F

Genes: 2064

Variants: S310F

[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: S310F | Summary: The S310F mutation was identified in a bladder cancer cell line, and its expression was analyzed through molecular techniques, indicating an alteration in molecular function.

Gene→Variant (gene-first): 2064:S310 2064:S310F

Genes: 2064

Variants: S310 S310F

[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: S310F | Summary: The S310F mutation is mentioned in the context of a bladder cancer cell line, indicating that it alters the molecular or biochemical function of HER2. Evidence Type: Oncogenic | Mutation: S310F | Summary: The presence of the S310F mutation in a bladder cancer cell line suggests that it may contribute to tumor development or progression.

Gene→Variant (gene-first): 2064:S310F

Genes: 2064

Variants: S310F

[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 2

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: S310F | Summary: The S310F mutant is not reactive to Pertuzumab, indicating a potential resistance to this therapy, while it retains binding to Trastuzumab, suggesting a correlation with treatment response. Evidence Type: Functional | Mutation: S310F | Summary: The S310F mutation alters the reactivity of the protein, affecting its binding properties with specific antibodies, which indicates a change in molecular function.

Gene→Variant (gene-first): 2064:S310F

Genes: 2064

Variants: S310F

[Paragraph-level] PMCID: PMC5762309 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: V559D | Summary: The KIT V559D mutation is identified as a primary gain-of-function mutation in Gastrointestinal Stromal Tumors (GISTs), contributing to tumor development. Evidence Type: Functional | Mutation: V559D | Summary: The V559D mutation alters molecular function, as evidenced by its selectivity and efficacy in biochemical assays and signaling pathways. Evidence Type: Oncogenic | Mutation: L576P | Summary: The L576P mutation is mentioned as a primary mutant in the context of selective inhibition, indicating its role in tumor progression. Evidence Type: Oncogenic | Mutation: T670I | Summary: The T670I mutation is classified as a secondary mutant, contributing to tumor development in the context of selective inhibition. Evidence Type: Oncogenic | Mutation: V654A | Summary: The V654A mutation is noted as a secondary mutant involved in tumor progression, as indicated by its context in selective inhibition. Evidence Type: Oncogenic | Mutation: N822K | Summary: The N822K mutation is mentioned in the context of activation loop mutations, suggesting its contribution to tumor development. Evidence Type: Oncogenic | Mutation: D816V | Summary: The D816V mutation is described as an activation loop mutation, indicating its role in tumor progression.

Gene→Variant (gene-first): 3815:D816V 3815:L576P 3815:N822K 3815:T670I 3815:V559D 3815:V654A

Genes: 3815

Variants: D816V L576P N822K T670I V559D V654A

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: V559D | Summary: The variant KIT V559D is associated with a specific response to the inhibitor CHMFL-KIT-031, demonstrating its potential predictive value for therapy effectiveness. Evidence Type: Functional | Mutation: V559D | Summary: The KIT V559D variant alters the molecular function of the kinase, as evidenced by its impact on auto-phosphorylation and downstream signaling pathways in response to treatment.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 7

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: V559D | Summary: The V559D mutation is associated with strong binding to the inhibitor CHMFL-KIT-031, suggesting its role in tumor development or progression. Evidence Type: Functional | Mutation: L576P | Summary: The L576P mutation is mentioned in the context of binding assays, indicating that it alters molecular or biochemical function. Evidence Type: Functional | Mutation: A829P | Summary: The A829P mutation is also discussed in relation to binding assays, suggesting it alters molecular or biochemical function.

Gene→Variant (gene-first): 3815:A829P 3815:L576P 3815:V559D

Genes: 3815

Variants: A829P L576P V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: V559D | Summary: The V559D mutation alters the phosphorylation of KIT at specific sites, indicating a change in molecular function related to the mutant's response to treatment. Evidence Type: Oncogenic | Mutation: V559D | Summary: The V559D mutation contributes to tumor development or progression as it is associated with the anti-proliferative effects observed in transformed BaF3 cells.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: V559D | Summary: The V559D mutation alters the molecular function of the KIT protein, as indicated by its role in auto-phosphorylation in the context of the study.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 2

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: V559D | Summary: The V559D mutation alters the molecular function of the KIT protein, as indicated by the selective inhibition of cell proliferation in BaF3-TEL-KIT-V559D cells. Evidence Type: Oncogenic | Mutation: V559D | Summary: The V559D mutation contributes to tumor development or progression, as it is associated with the proliferation of BaF3-TEL-KIT-V559D cells.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5002925 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Oncogenic, Functional

Summary: Evidence Type: Predictive | Mutation: p.L755S | Summary: The ERBB2 p.L755S mutation was used to guide treatment with trastuzumab, indicating a correlation with therapy response. Evidence Type: Oncogenic | Mutation: p.L755S | Summary: The presence of the ERBB2 p.L755S mutation suggests it may contribute to tumor development or progression in colorectal cancer. Evidence Type: Functional | Mutation: p.L755S | Summary: The mutation is described in the context of its biological significance, indicating an alteration in molecular function. Evidence Type: Oncogenic | Mutation: p.N581S | Summary: The BRAF p.N581S mutation is mentioned as a genetic driver event, suggesting its role in tumor development or progression. Evidence Type: Oncogenic | Mutation: p.Q1429fs | Summary: The APC p.Q1429fs mutation is identified as a genetic driver event, indicating its contribution to tumor development or progression.

Gene→Variant (gene-first): 2064:p.L755S 673:p.N581S 324:p.Q1429fs

Genes: 2064 673 324

Variants: p.L755S p.N581S p.Q1429fs

[Paragraph-level] PMCID: PMC5002925 Section: RESULTS PassageIndex: 6

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: p.L755S | Summary: The ERBB2 p.L755S mutation is a heterozygous somatic mutation that contributes to tumor development or progression, as indicated by its presence in tumor samples and its allele frequency. Evidence Type: Oncogenic | Mutation: p.Q1429fs | Summary: The APC p.Q1429fs mutation is a heterozygous somatic mutation that is associated with tumor development or progression, as it was detected in tumor samples. Evidence Type: Oncogenic | Mutation: p.N518S | Summary: The BRAF p.N518S mutation is a heterozygous somatic mutation that contributes to tumor development or progression, as evidenced by its detection in tumor samples. Evidence Type: Functional | Mutation: p.N581S | Summary: The BRAF p.N581S mutation was verified and its biological effect was predicted using algorithms, indicating that it alters molecular or biochemical function.

Gene→Variant (gene-first): 2064:p.L755S 673:p.N518S 673:p.N581S 324:p.Q1429fs

Genes: 2064 673 324

Variants: p.L755S p.N518S p.N581S p.Q1429fs

[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 24

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: Q61H | Summary: The KRAS Q61H mutation is associated with the emergence of subclonal mutations contributing to tumor development and progression, as indicated by its detection prior to disease progression. Evidence Type: Oncogenic | Mutation: Q61L | Summary: The KRAS Q61L mutation is part of the multiple subclonal KRAS mutations identified, which are implicated in tumor development and progression. Evidence Type: Oncogenic | Mutation: G12N | Summary: The KRAS G12N mutation is included among the subclonal mutations that contribute to tumor development and progression. Evidence Type: Oncogenic | Mutation: G13D | Summary: The KRAS G13D mutation is identified as a subclonal mutation that plays a role in tumor development and progression. Evidence Type: Oncogenic | Mutation: G12D | Summary: The NRAS G12D mutation is part of the identified mutations that contribute to tumor development and progression. Evidence Type: Functional | Mutation: A163G | Summary: The KDR A163G mutation is mentioned in the context of targeted sequencing, suggesting it may alter molecular or biochemical function. Evidence Type: Functional | Mutation: R106H | Summary: The MSH6 R106H mutation is identified in the context of targeted sequencing, indicating a potential alteration in molecular or biochemical function.

Gene→Variant (gene-first): 3791:A163G 3845:G12D 3845:G12N 3845:G13D 3845:Q61H 4893:Q61L 79811:R106H 673:V600E

Genes: 3791 3845 4893 79811 673

Variants: A163G G12D G12N G13D Q61H Q61L R106H V600E

[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: V769dupASV | Summary: The V769dupASV mutation shows altered sensitivity to dacomitinib, indicating a correlation with response to therapy. Evidence Type: Functional | Mutation: V769dupASV | Summary: The V769dupASV mutation affects the biochemical function of EGFR, as evidenced by the differential inhibition of phosphorylated EGFR in response to dacomitinib.

Gene→Variant (gene-first): 1956:V769dupASV

Genes: 1956

Variants: V769dupASV

[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 5

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: D770_N771insSVD | Summary: The D770_N771insSVD mutation is associated with sensitivity to mobocertinib and poziotinib, indicating its predictive value for response to these therapies. Evidence Type: Predictive | Mutation: V769dupASV | Summary: The V769dupASV mutation shows sensitivity to mobocertinib and poziotinib, suggesting it has predictive implications for treatment response. Evidence Type: Functional | Mutation: Y764insFQEA | Summary: The Y764insFQEA mutation is described as pan-sensitive to all EGFR TKIs tested, indicating a functional alteration in response to these therapies.

Gene→Variant (gene-first): 1956:D770_N771insSVD 1956:V769dupASV 1956:Y764insFQEA

Genes: 1956

Variants: D770_N771insSVD V769dupASV Y764insFQEA

[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: G770 | Summary: The passage discusses the preclinical characterization of an EGFR Exon 20 Insertion Mutant with a G770 equivalence, indicating that this variant alters molecular or biochemical function.

Gene→Variant (gene-first): 1956:G770

Genes: 1956

Variants: G770

[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: G770 | Summary: The G770 mutation is part of the EGFR exon 20 insertion mutations, which are known to contribute to tumor development or progression. Evidence Type: Functional | Mutation: G770 | Summary: The G770 mutation alters molecular or biochemical function as it is associated with changes in the EGFR protein due to the insertion mutations.

Gene→Variant (gene-first): 1956:G770

Genes: 1956

Variants: G770

[Paragraph-level] PMCID: PMC3244026 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: V345fs | Summary: The V345fs ETV6 mutant is functionally inactive, showing no transcriptional repression activity and exhibiting dominant-negative activity compared to wild-type ETV6. Evidence Type: Functional | Mutation: N356fs | Summary: The N356fs ETV6 mutant is functionally inactive, demonstrating a lack of transcriptional repression activity and exhibiting dominant-negative activity compared to wild-type ETV6. Evidence Type: Functional | Mutation: Y103fs | Summary: The Y103fs ETV6 mutant is functionally inactive, with no transcriptional repression activity and exhibiting dominant-negative activity compared to wild-type ETV6. Evidence Type: Functional | Mutation: S105fs | Summary: The S105fs ETV6 mutant is functionally inactive, showing no transcriptional repression activity and exhibiting dominant-negative activity compared to wild-type ETV6.

Gene→Variant (gene-first): 2120:N356fs 2120:S105fs 2120:V345fs 2120:Y103fs

Genes: 2120

Variants: N356fs S105fs V345fs Y103fs

[Paragraph-level] PMCID: PMC3244026 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: Y103fs | Summary: The Y103fs mutation leads to the expression of N-terminal truncated protein products that alter the molecular function of the ETV6 protein. Evidence Type: Functional | Mutation: S105fs | Summary: The S105fs mutation results in the activation of internal translation initiation sites and the expression of truncated ETV6 protein products, indicating a change in molecular function. Evidence Type: Functional | Mutation: V345fs | Summary: The V345fs mutation causes the expression of C-terminal truncated polypeptides, which alters the molecular function of the ETV6 protein. Evidence Type: Functional | Mutation: N356fs | Summary: The N356fs mutation results in the expression of C-terminal truncated ETV6 proteins, indicating a change in molecular function.

Gene→Variant (gene-first): 2120:N356fs 2120:S105fs 2120:V345fs 2120:Y103fs

Genes: 2120

Variants: N356fs S105fs V345fs Y103fs

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: c.236A>G (p.Tyr79Cys) | Summary: The c.236A>G (p.Tyr79Cys) variant is described as a somatic variant in renal cell carcinomas (RCCs) and contributes to tumor development in VHL-independent renal tumorigenesis. Evidence Type: Oncogenic | Mutation: c.274G>A (p.Glu92Lys) | Summary: The c.274G>A (p.Glu92Lys) variant is identified as a somatic variant in RCC, contributing to tumor development. Evidence Type: Oncogenic | Mutation: c.74A>T (p.Asp25Val) | Summary: The c.74A>T (p.Asp25Val) variant is reported as a somatic variant in RCC, indicating its role in tumor development. Evidence Type: Oncogenic | Mutation: c.311T>A (p.Leu104Gln) | Summary: The c.311T>A (p.Leu104Gln) variant is noted as a somatic variant in RCC, suggesting its involvement in tumor progression. Evidence Type: Functional | Mutation: c.261_272del (p.Thr88_Pro91del) | Summary: The c.261_272del (p.Thr88_Pro91del) variant is described as an in-frame deletion that alters molecular function, contributing to the understanding of ELOC variants in RCC.

Gene→Variant (gene-first): 3091:c.236A>G 6921:c.261_272del 5979:c.274G>A 6921:c.311T>A 3855:c.74A>T 3855:p.Asp25Val 7409:p.Glu92Lys 6921:p.Leu104Gln 6921:p.Thr88_Pro91del 3091:p.Tyr79Cys

Genes: 3091 6921 5979 3855 7409

Variants: c.236A>G c.261_272del c.274G>A c.311T>A c.74A>T p.Asp25Val p.Glu92Lys p.Leu104Gln p.Thr88_Pro91del p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: c.236A>G | Summary: The c.236A>G variant is associated with mosaicism, suggesting it alters molecular or biochemical function. Evidence Type: Functional | Mutation: p.Tyr79Cys | Summary: The p.Tyr79Cys variant is associated with mosaicism, indicating it alters molecular or biochemical function.

Gene→Variant (gene-first): 3091:236A>G 3091:c.236A>G 3091:p.Tyr79Cys

Genes: 3091

Variants: 236A>G c.236A>G p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: c.236A>G (p.Tyr79Cys) | Summary: The de novo missense variant c.236A>G (p.Tyr79Cys) alters the molecular function of the ELOC gene, as the Tyr79 residue is critical for forming a hydrogen bond with the Pro154 residue within the pVHL alpha domain. Evidence Type: Oncogenic | Mutation: c.236A>G (p.Tyr79Cys) | Summary: The missense variant c.236A>G (p.Tyr79Cys) is implicated in tumor development due to its location in the tetramerization domain of the ELOC gene, which is essential for its function in the context of VHL disease.

Gene→Variant (gene-first): 3091:Tyr79 3091:Y79 3091:c.236A>G 3091:p.Tyr79Cys

Genes: 3091

Variants: Tyr79 Y79 c.236A>G p.Tyr79Cys

[Paragraph-level] PMCID: PMC6594036 Section: RESULTS PassageIndex: 8

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: 2690A > G | Summary: The mutation 2690A > G in the TEK gene is associated with tumor development or progression. Evidence Type: Oncogenic | Mutation: c.2752A > G | Summary: The mutation c.2752A > G in the TEK gene is associated with tumor development or progression. Evidence Type: Functional | Mutation: Arg918Cys | Summary: The mutation Arg918Cys is likely to alter molecular or biochemical function. Evidence Type: Functional | Mutation: Tyr897Cys | Summary: The mutation Tyr897Cys is likely to alter molecular or biochemical function.

Gene→Variant (gene-first): 7010:2690A > G 3845:Arg918Cys 7010:Tyr897Cys 7010:c.2752A > G

Genes: 7010 3845

Variants: 2690A > G Arg918Cys Tyr897Cys c.2752A > G

[Paragraph-level] PMCID: PMC7612117 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional, Predictive, Prognostic

Summary: Evidence Type: Oncogenic | Mutation: p.L1363P | Summary: The BRCA1 p.L1363P variant contributes to tumor development, as it leads to the acceleration of mammary tumors in genetically engineered mice, indicating its role in cancer progression. Evidence Type: Functional | Mutation: p.L1363P | Summary: The BRCA1 p.L1363P variant disrupts the interaction with PALB2 and results in HRR incompetence, demonstrating an alteration in molecular function. Evidence Type: Predictive | Mutation: p.L1363P | Summary: The BRCA1 p.L1363P variant is responsive to cisplatin and PARP inhibition, indicating its potential correlation with treatment response. Evidence Type: Prognostic | Mutation: p.L1363P | Summary: The presence of the BRCA1 p.L1363P variant is associated with distinct histopathological features and stable DNA copy number profiles in tumors, which may correlate with disease outcome.

Gene→Variant (gene-first): 7158:p.L1363P

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 24

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: H1047 | Summary: The mutation H1047 is associated with altered lipid binding capabilities among the p110 isoforms, indicating a change in molecular function. Evidence Type: Functional | Mutation: H1047L | Summary: The mutation H1047L shows increased lipid binding levels compared to other p110 isoforms, suggesting a modification in biochemical function.

Gene→Variant (gene-first): 5290:H1047 5290:H1047L

Genes: 5290

Variants: H1047 H1047L

[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 22

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: H1047R | Summary: The H1047R mutation in p110alpha appears to induce a global conformational change that may impact the molecular activity of the kinase C-lobe, suggesting a functional alteration in its biochemical properties.

Gene→Variant (gene-first): 5290:H1047R

Genes: 5290

Variants: H1047R

[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 20

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: C420R | Summary: The C420R mutation alters the molecular interactions within the C2 domain, potentially affecting lipid binding due to changes in hydrophobicity. Evidence Type: Functional | Mutation: N564D | Summary: The N564D mutation modifies the polar contacts in the C2 domain, which may influence the interaction with phospholipid headgroups. Evidence Type: Functional | Mutation: E545K | Summary: The E545K mutation disrupts contacts in the C2/helical-nSH2 region, potentially exposing hydrophobic areas that could affect lipid binding.

Gene→Variant (gene-first): 5290:C420 5290:C420R 5290:E545K 5295:N345 5295:N564 5295:N564D

Genes: 5290 5295

Variants: C420 C420R E545K N345 N564 N564D

[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 19

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: G1049R | Summary: The G1049R mutation alters molecular function by exhibiting high levels of hydrophobic and electrostatic binding to lipids upon phosphopeptide activation. Evidence Type: Functional | Mutation: H1047L | Summary: The H1047L mutation alters molecular function by exhibiting high levels of hydrophobic and electrostatic binding to lipids upon phosphopeptide activation. Evidence Type: Functional | Mutation: H1047R | Summary: The H1047R mutation alters molecular function by exhibiting high levels of hydrophobic and electrostatic binding to lipids upon phosphopeptide activation.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047L 5290:H1047R

Genes: 5290

Variants: G1049R H1047L H1047R

[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 18

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: C420R | Summary: The C420R mutation alters molecular function by displaying high levels of hydrophobic interaction with neutral lipids in the basal state. Evidence Type: Functional | Mutation: E545K | Summary: The E545K mutation alters molecular function by displaying high levels of hydrophobic interaction with neutral lipids in the basal state. Evidence Type: Functional | Mutation: N564D | Summary: The N564D mutation alters molecular function by displaying high levels of hydrophobic interaction with neutral lipids in the basal state.

Gene→Variant (gene-first): 5290:C420R 5290:E545K 5295:N564D

Genes: 5290 5295

Variants: C420R E545K N564D

[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K942Q | Summary: The K942Q mutation is associated with altered lipid binding properties, indicating a change in molecular function related to lipid interactions. Evidence Type: Functional | Mutation: R949D | Summary: The R949D mutation shows much reduced binding to anionic lipids, suggesting an alteration in molecular function related to lipid interactions.

Gene→Variant (gene-first): 5294:K942Q 5294:R949D

Genes: 5294

Variants: K942Q R949D

[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: D915N | Summary: The D915N mutation in the catalytic DRH motif of p110alpha is associated with altered molecular function, specifically in the context of lipid binding and activation of the p110/p85 complex. Evidence Type: Oncogenic | Mutation: D915N | Summary: The D915N mutation is described as a cancer-linked mutation, indicating its contribution to tumor development or progression.

Gene→Variant (gene-first): 5290:D915N

Genes: 5290

Variants: D915N

[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: deletion of residues 1051-1068 | Summary: The deletion of residues 1051-1068 in p110alpha alters its molecular function by abrogating lipid kinase activity and lipid binding, indicating its functional importance.

Gene→Variant (gene-first): 5290:deletion of residues 1051-1068

Genes: 5290

Variants: deletion of residues 1051-1068

[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 6

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: H1047R | Summary: The H1047R mutation in p110alpha is described as an oncogenic mutant, indicating its contribution to tumor development or progression. Evidence Type: Functional | Mutation: H1047R | Summary: The passage discusses structural features of the H1047R mutant, suggesting that this variant alters molecular or biochemical function, particularly in relation to its conformation and interactions within the protein structure.

Gene→Variant (gene-first): 5290:H1047R

Genes: 5290

Variants: H1047R

[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K942 | Summary: The mutation K942 is described as being important for p110gamma recognizing the substrate PtdIns(4,5)P2 head group, indicating that it alters molecular or biochemical function. Evidence Type: Functional | Mutation: R949 | Summary: The mutation R949 is also noted for its importance in the recognition of the substrate PtdIns(4,5)P2 head group, suggesting it alters molecular or biochemical function.

Gene→Variant (gene-first): 5294:K942 5294:R949

Genes: 5294

Variants: K942 R949

[Paragraph-level] PMCID: PMC3378484 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: E545K | Summary: The E545K mutant shows the highest basal activity and lipid binding, mimicking the activated wild-type p110alpha, indicating its role in tumor development. Evidence Type: Oncogenic | Mutation: H1047R | Summary: The H1047R mutant exhibits increased basal kinase activities and lipid binding, contributing to tumor progression. Evidence Type: Oncogenic | Mutation: C420R | Summary: The C420R mutation shows increased basal kinase activity and lipid binding, suggesting its involvement in oncogenesis. Evidence Type: Oncogenic | Mutation: M1043I | Summary: The M1043I mutation is associated with increased basal kinase activity and lipid binding, indicating its oncogenic potential. Evidence Type: Oncogenic | Mutation: H1047L | Summary: The H1047L mutation demonstrates increased basal kinase activity and lipid binding, contributing to tumor development. Evidence Type: Oncogenic | Mutation: G1049R | Summary: The G1049R mutation shows increased basal kinase activity and lipid binding, suggesting its role in oncogenesis. Evidence Type: Functional | Mutation: N564D | Summary: The N564D mutation is associated with altered lipid binding activities, indicating a change in molecular function.

Gene→Variant (gene-first): 5290:C420R 5290:E545K 5290:G1049R 5290:H1047L 5290:H1047R 5290:M1043I 5295:N564D

Genes: 5290 5295

Variants: C420R E545K G1049R H1047L H1047R M1043I N564D

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 8

Evidence Type(s): Predictive, Functional, Oncogenic

Summary: Evidence Type: Predictive | Mutation: D835 | Summary: The D835 mutation is associated with sensitivity to type II inhibitors, suggesting that certain D835 mutants may respond to therapy despite being excluded from clinical trials. Evidence Type: Functional | Mutation: D835 | Summary: The D835 residue is critical for stabilizing the inactive conformation of FLT3, and mutations at this site affect the molecular interactions necessary for type II inhibitor binding. Evidence Type: Oncogenic | Mutation: D835 | Summary: The D835 mutation contributes to tumor development by influencing the kinase's conformation and resistance to inhibitors. Evidence Type: Predictive | Mutation: D835N/E | Summary: The D835N/E mutations may retain sensitivity to type II FLT3 TKIs, indicating a potential response to therapy. Evidence Type: Functional | Mutation: D835N/E | Summary: The D835N/E mutations preserve critical structural features necessary for the binding of type II inhibitors, affecting the molecular function of FLT3. Evidence Type: Oncogenic | Mutation: D835N/E | Summary: The D835N/E mutations are implicated in tumor progression by maintaining a conformation that allows for continued kinase activity despite treatment.

Gene→Variant (gene-first): 2322:D835 2322:D835N/E

Genes: 2322

Variants: D835 D835N/E

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: D835H | Summary: The D835H mutation is associated with resistance to type II inhibitors, indicating a correlation with treatment response and sensitivity to specific therapies. Evidence Type: Functional | Mutation: D835H | Summary: The D835H mutation alters molecular interactions, specifically affecting hydrogen bond formation and binding mode accommodation, which impacts its biochemical function.

Gene→Variant (gene-first): 2322:D835H

Genes: 2322

Variants: D835H

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: D835Y | Summary: The D835Y mutation alters molecular interactions, as it is described as having large and bulky hydrophobic amino acid residues that affect hydrogen bonding and steric compatibility. Evidence Type: Functional | Mutation: D835V | Summary: The D835V mutation is characterized by large and bulky hydrophobic amino acid residues, impacting molecular interactions and steric compatibility with the protein structure.

Gene→Variant (gene-first): 2322:D835Y/V

Genes: 2322

Variants: D835Y/V

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: D835E/N | Summary: The D835E/N mutations are predicted to preserve hydrogen bonding interactions that maintain the structural integrity of the protein, suggesting an alteration in molecular function related to inhibitor binding. Evidence Type: Oncogenic | Mutation: D835E/N | Summary: The D835E/N mutations contribute to tumor development by preserving the DFG-out conformation, which is associated with sensitivity to type II inhibitors, indicating a role in cancer progression.

Gene→Variant (gene-first): 2322:D835 2322:D835E/N

Genes: 2322

Variants: D835 D835E/N

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 4

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: D835 | Summary: The D835 mutation is associated with resistance to type II inhibitors, suggesting a correlation with treatment response or resistance. Evidence Type: Functional | Mutation: D835 | Summary: The D835 mutation impacts the short alpha-helix, which is coupled to the drug-binding site, indicating an alteration in molecular function.

Gene→Variant (gene-first): 2322:D835

Genes: 2322

Variants: D835

[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: D835 | Summary: The D835 mutation is predicted to play a critical role in stabilizing the DFG-out conformation of the kinase AL by serving as an amino-terminal capping residue for a short alpha-helix, indicating its impact on molecular function.

Gene→Variant (gene-first): 2322:D835

Genes: 2322

Variants: D835

[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 16

Evidence Type(s): Predictive, Oncogenic, Functional

Summary: Evidence Type: Predictive | Mutation: BRAFV600E | Summary: The BRAFV600E mutation is associated with venetoclax resistance, indicating a correlation with treatment response. Evidence Type: Oncogenic | Mutation: BRAFV600E | Summary: The BRAFV600E mutation contributes to tumor development and progression, as evidenced by its role in inducing venetoclax resistance in cell lines. Evidence Type: Functional | Mutation: p.W110 | Summary: The p.W110 mutation in CDKN2A/B is a nonsense mutation that likely alters the molecular function of the gene, contributing to cancer-related processes.

Gene→Variant (gene-first): 673:BRAFV600E 673:p.V600E 7157:p.W110*

Genes: 673 7157

Variants: BRAFV600E p.V600E p.W110*

[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 16

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: V871I | Summary: The variant EPHB4-V871I is associated with a response to treatment with TK inhibitors, indicating its predictive value in therapy sensitivity. Evidence Type: Functional | Mutation: V871I | Summary: The variant EPHB4-V871I alters the phenotype in neuroblastoma (NB) cell lines, suggesting a functional impact on molecular or biochemical processes.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: V871I | Summary: The EPHB4-V871I variant is associated with increased expression levels of downstream target genes and enhanced phosphorylation of the ERK1-2 pathway, indicating an alteration in molecular function. Evidence Type: Oncogenic | Mutation: V871I | Summary: The EPHB4-V871I variant contributes to tumor development or progression as suggested by its impact on downstream signaling pathways and gene expression.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: V871I | Summary: The EPHB4-V871I variant alters molecular function by increasing the expression of target genes and enhancing the phosphorylation of the ERK1-2 pathway.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: V871I | Summary: The V871I mutation in EPHB4 alters molecular function, as indicated by the increased number of colonies formed in the colony formation assay in soft agar compared to wild type and empty vector controls.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: V871I | Summary: The EPHB4-V871I variant alters the migration properties of cells, indicating a change in molecular or biochemical function.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: V871I | Summary: The EPHB4-V871I variant demonstrates increased migration properties in wound-healing experiments, indicating an alteration in molecular function related to cell migration. Evidence Type: Oncogenic | Mutation: V871I | Summary: The increased migration potential of EPHB4-V871I suggests that this somatic variant may contribute to tumor development or progression by enhancing cell motility.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: V871I | Summary: The V871I mutation in EPHB4 is associated with altered cellular proliferation, as indicated by increased propagation rates in cells overexpressing this variant compared to controls. Evidence Type: Oncogenic | Mutation: V871I | Summary: The V871I mutation in EPHB4 contributes to tumor development and progression, as suggested by its involvement in increased proliferation rates in cancer cell lines.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: V871I | Summary: The V871I mutation alters the molecular function related to the proliferation and migration of neuroblastoma (NB) cell lines.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: V871I | Summary: The EPHB4-V871I variant was functionally characterized, showing that it does not impair EPHB4 expression at the mRNA and protein levels.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

[Paragraph-level] PMCID: PMC11253285 Section: RESULTS PassageIndex: 18

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: S4D | Summary: The S4D mutation is associated with a response to SRA737 in combination with PARP inhibitors, indicating its potential predictive value for therapy response. Evidence Type: Functional | Mutation: S4D | Summary: The S4D mutation appears to alter the molecular response to treatment, as indicated by the higher percentage of pCHK1 positive cells in tumors treated with the combination therapy.

Gene→Variant (gene-first): 142:S4D

Genes: 142

Variants: S4D

[Paragraph-level] PMCID: PMC3727232 Section: RESULTS PassageIndex: 6

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: p.R132H | Summary: The IDH1 mutation p.R132H is associated with tumor development or progression in the context of oligodendroglioma. Evidence Type: Functional | Mutation: p.V676fs | Summary: The CIC mutation p.V676fs alters molecular or biochemical function, contributing to the tumor's genetic profile. Evidence Type: Functional | Mutation: p.S726R | Summary: The CIC mutation p.S726R alters molecular or biochemical function, contributing to the tumor's genetic profile. Evidence Type: Functional | Mutation: p.D1722V | Summary: The CHD2 mutation p.D1722V alters molecular or biochemical function, contributing to the tumor's genetic profile. Evidence Type: Functional | Mutation: p.P101L | Summary: The STYK1 mutation p.P101L alters molecular or biochemical function, contributing to the tumor's genetic profile.

Gene→Variant (gene-first): 1106:p.D1722V 1029:p.P101L 3417:p.R132H 23152:p.S726R 23152:p.V676fs

Genes: 1106 1029 3417 23152

Variants: p.D1722V p.P101L p.R132H p.S726R p.V676fs

[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: p.Ala636Pro | Summary: The variant p.Ala636Pro is associated with a significant depletion of deleterious scores in a functional assay, indicating that it alters molecular or biochemical function. Evidence Type: Oncogenic | Mutation: p.Ala636Pro | Summary: The variant p.Ala636Pro is implicated in the context of bi-allelic MMR loss, which is known to contribute to tumor development in pediatric-onset cancer syndromes such as Lynch syndrome.

Gene→Variant (gene-first): 4436:p.Ala636Pro

Genes: 4436

Variants: p.Ala636Pro

[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: p.Ala636Pro | Summary: The p.Ala636Pro mutant variant of MSH2 was shown to restore 6-TG sensitivity in a functional assay, indicating that it alters the molecular function of the MMR machinery. Evidence Type: Oncogenic | Mutation: p.Ala636Pro | Summary: The enrichment of barcodes linked to the pathogenic variant p.Ala636Pro in mixed cultures suggests that this somatic variant contributes to tumor development or progression by affecting MMR function.

Gene→Variant (gene-first): 4436:p.Ala636Pro

Genes: 4436

Variants: p.Ala636Pro

[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: p.Ala636Pro | Summary: The p.Ala636Pro variant is associated with a destabilizing effect on MSH2 protein expression, indicating an alteration in molecular function. Evidence Type: Oncogenic | Mutation: p.Ala636Pro | Summary: The p.Ala636Pro variant is described as a pathogenic founder allele, suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): 4436:p.Ala636Pro

Genes: 4436

Variants: p.Ala636Pro

[Paragraph-level] PMCID: PMC3383766 Section: RESULTS PassageIndex: 21

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: V777L | Summary: The V777L mutation in ERBB2 is associated with tumor development, particularly in the context of gefitinib-activating mutations in lung cancer. Evidence Type: Oncogenic | Mutation: A829V | Summary: The A829V mutation in DDR1 is implicated in tumor development and progression. Evidence Type: Oncogenic | Mutation: R611C | Summary: The R611C mutation in DDR1 contributes to tumor development. Evidence Type: Oncogenic | Mutation: E583D | Summary: The E583D mutation in DDR2 is associated with oncogenic activity. Evidence Type: Oncogenic | Mutation: D735H | Summary: The D735H mutation in CSF1R is linked to tumor progression. Evidence Type: Oncogenic | Mutation: M875L | Summary: The M875L mutation in CSF1R contributes to tumor development. Evidence Type: Oncogenic | Mutation: E924K | Summary: The E924K mutation in PDGFRA is associated with oncogenic behavior. Evidence Type: Functional | Mutation: C77F | Summary: The C77F mutation in AKT1 alters molecular function. Evidence Type: Functional | Mutation: S11F | Summary: The S11F mutation in AKT2 affects molecular function. Evidence Type: Functional | Mutation: S375F | Summary: The S375F mutation in RPS6KB1 alters biochemical function.

Gene→Variant (gene-first): 780:A829V 207:C77F 405:D735H 3084:E583D 2048:E924K 5156:M875L 780:R611C 208:S11F 3169:S375F 2064:V777L

Genes: 780 207 405 3084 2048 5156 208 3169 2064

Variants: A829V C77F D735H E583D E924K M875L R611C S11F S375F V777L

[Paragraph-level] PMCID: PMC3383766 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: M294K | Summary: The M294K mutation in GATA3 is associated with functional inactivation, as indicated by the presence of truncation events and other mutations in the gene. Evidence Type: Oncogenic | Mutation: M294K | Summary: The recurrent M294K mutation in GATA3 suggests a role in tumor development, reinforcing the conclusion that GATA3 acts as a tumor suppressor.

Gene→Variant (gene-first): 2625:M294K

Genes: 2625

Variants: M294K

[Paragraph-level] PMCID: PMC3383766 Section: RESULTS PassageIndex: 7

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: G168E | Summary: The G168E mutation in RUNX1 is implicated in tumor development and progression, particularly in the M2 subtype of AML. Evidence Type: Oncogenic | Mutation: R166Q | Summary: The R166Q mutation in RUNX1 contributes to tumor development and is associated with the M2 subtype of AML. Evidence Type: Oncogenic | Mutation: R169K | Summary: The R169K mutation in RUNX1 is involved in tumor progression and is relevant to the M2 subtype of AML. Evidence Type: Oncogenic | Mutation: K700E | Summary: The K700E mutation in SF3B1 is implicated in tumor development and is associated with myelodysplastic syndromes (MDS) and chronic lymphocytic leukemia (CLL). Evidence Type: Oncogenic | Mutation: K666Q | Summary: The K666Q mutation in SF3B1 contributes to tumor development and is relevant in the context of MDS and CLL. Evidence Type: Functional | Mutation: S184L | Summary: The S184L mutation in MAP2K4 alters molecular function, likely affecting splicing and kinase pathway activation.

Gene→Variant (gene-first): 9757:G168E 23451:K666Q 23451:K700E 4216:N104S 861:R166Q 1588:R169K 51742:S184L

Genes: 9757 23451 4216 861 1588 51742

Variants: G168E K666Q K700E N104S R166Q R169K S184L

[Paragraph-level] PMCID: PMC7099049 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Prognostic

Summary: Evidence Type: Functional | Mutation: rs16879870 | Summary: The allele A of rs16879870 is associated with an increased mRNA expression level of gene GJB7, indicating a potential functional impact on gene expression. Evidence Type: Functional | Mutation: rs854936 | Summary: The allele C of rs854936 is associated with an increased mRNA level of gene RTN4R, suggesting a functional role in gene expression. Evidence Type: Prognostic | Mutation: rs16879870 | Summary: Higher expression of GJB7 in cancer tissues correlates with worse prognosis in HNSCC patients, indicating a prognostic significance of this variant. Evidence Type: Prognostic | Mutation: rs854936 | Summary: Increased expression of RTN4R in cancer tissues is associated with worse prognosis in HNSCC patients, highlighting its prognostic relevance.

Gene→Variant (gene-first): NA:rs16879870 NA:rs854936

Genes: NA

Variants: rs16879870 rs854936

[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: A289V | Summary: The A289V mutation alters molecular function, as it is associated with increased tyrosine phosphorylation in response to EGF stimulation in murine hematopoietic cells. Evidence Type: Functional | Mutation: G598V | Summary: The G598V mutation alters molecular function, as it is associated with increased tyrosine phosphorylation in response to EGF stimulation in murine hematopoietic cells. Evidence Type: Functional | Mutation: L861Q | Summary: The L861Q mutation alters molecular function, as it is associated with increased tyrosine phosphorylation in response to EGF stimulation in murine hematopoietic cells. Evidence Type: Functional | Mutation: R108K | Summary: The R108K mutation alters molecular function, as it is associated with increased tyrosine phosphorylation in response to EGF stimulation in murine hematopoietic cells. Evidence Type: Functional | Mutation: T263P | Summary: The T263P mutation alters molecular function, as it is associated with increased tyrosine phosphorylation in response to EGF stimulation in murine hematopoietic cells.

Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:L861Q 1956:R108K 1956:T263P

Genes: 1956

Variants: A289V G598V L861Q R108K T263P

[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: A289V | Summary: The A289V mutation in EGFR shows a marked increase in receptor autophosphorylation, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: T263P | Summary: The T263P mutation in EGFR is part of a panel of missense mutants that exhibit increased phosphotyrosine content, suggesting a change in biochemical function. Evidence Type: Functional | Mutation: G598V | Summary: The G598V mutation is included in a panel of EGFR missense mutants that demonstrate increased phosphotyrosine content, indicating a functional alteration. Evidence Type: Functional | Mutation: L861Q | Summary: The L861Q mutation is part of a group of EGFR missense mutants that show increased phosphotyrosine content, reflecting a change in molecular function.

Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:L861Q 1956:T263P

Genes: 1956

Variants: A289V G598V L861Q T263P

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: p.Asn345Thr | Summary: The p.Asn345Thr mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Oncogenic | Mutation: p.Glu545Asp | Summary: The p.Glu545Asp mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Oncogenic | Mutation: p.Gln546His | Summary: The p.Gln546His mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Oncogenic | Mutation: p.Asn345Lys | Summary: The p.Asn345Lys mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Oncogenic | Mutation: p.Glu545Lys | Summary: The p.Glu545Lys mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Oncogenic | Mutation: p.Glu545Gly | Summary: The p.Glu545Gly mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Oncogenic | Mutation: p.Gln546Lys | Summary: The p.Gln546Lys mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Oncogenic | Mutation: p.Gln546Pro | Summary: The p.Gln546Pro mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Oncogenic | Mutation: p.Tyr1021His | Summary: The p.Tyr1021His mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Functional | Mutation: p.Ala1035Thr | Summary: The p.Ala1035Thr mutation has been demonstrated to alter molecular function through a gain-of-function mechanism. Evidence Type: Functional | Mutation: p.Ala1035Val | Summary: The p.Ala1035Val mutation has been demonstrated to alter molecular function through a gain-of-function mechanism. Evidence Type: Oncogenic | Mutation: Glu545Ala | Summary: The Glu545Ala mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Oncogenic | Mutation: Glu545Lys | Summary: The Glu545Lys mutation is associated with a gain-of-function mechanism and contributes to tumor development.

Gene→Variant (gene-first): 5290:Glu545Ala 5290:Glu545Lys 5290:p.Ala1035Thr 5290:p.Ala1035Val 5290:p.Asn345Lys 5290:p.Asn345Thr 5290:p.Gln546His 5290:p.Gln546Lys 5290:p.Gln546Pro 5290:p.Glu545Asp 5290:p.Glu545Gly 5290:p.Glu545Lys 5290:p.Tyr1021Cys 7249:p.Tyr1021His

Genes: 5290 7249

Variants: Glu545Ala Glu545Lys p.Ala1035Thr p.Ala1035Val p.Asn345Lys p.Asn345Thr p.Gln546His p.Gln546Lys p.Gln546Pro p.Glu545Asp p.Glu545Gly p.Glu545Lys p.Tyr1021Cys p.Tyr1021His

[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: p.M90I | Summary: The p.M90I mutation in RIT1 is associated with human primary lung adenocarcinomas and is suggested to contribute to tumor development or progression based on its presence in 'oncogene-negative' lung cancer cell lines. Evidence Type: Functional | Mutation: p.M90I | Summary: The p.M90I mutation is being studied for its role in altering the molecular function of RIT1 in the context of human cancer pathogenesis.

Gene→Variant (gene-first): 6016:p.M90I

Genes: 6016

Variants: p.M90I

[Paragraph-level] PMCID: PMC3923676 Section: RESULTS PassageIndex: 16

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: E384X | Summary: The E384X mutation in ERRFI1 is described as a novel loss of function mutation that contributes to tumor development in the patient's metastatic, recurrent/refractory SIC. The evidence suggests nearly complete loss of function of ERRFI1 in the tumor, indicating its role in cancer progression. Evidence Type: Functional | Mutation: E384X | Summary: The E384X mutation results in nearly complete loss of function of the ERRFI1 protein, as indicated by the allele-specific expression data from the RNASeq analysis. This alteration in molecular function is significant in the context of the patient's tumor.

Gene→Variant (gene-first): 672:E384X

Genes: 672

Variants: E384X

[Paragraph-level] PMCID: PMC3923676 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: G C | Summary: The G C missense mutations in the DNAH5 gene are noted to alter the molecular function of the dynein protein, which is part of the microtubule-associated motor protein complex.

Gene→Variant (gene-first): 1767:G C

Genes: 1767

Variants: G C