[Paper-level Aggregated] PMCID: PMC11551396

Evidence Type(s): Functional

Summary: Mutation: N771insSVD | Summary: The N771insSVD variant alters the molecular function of EGFR, as it is involved in drug sensitivity and resistance mechanisms compared to wild-type EGFR.

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, and is also studied in the context of cocrystal structures with various inhibitors, indicating an alteration in molecular or biochemical function.

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.

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.

Gene→Variant (gene-first): EGFR(1956):N771insSVD EGFR(1956):L858R EGFR(1956):T790M EGFR(1956):V948R EGFR(1956):C797

Genes: EGFR(1956)

Variants: N771insSVD L858R T790M V948R C797

[Paper-level Aggregated] PMCID: PMC11253285

Evidence Type(s): Functional

Summary: 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. It is also associated with a response to SRA737 in combination with PARP inhibitors, indicating its potential predictive value for therapy response.

Gene→Variant (gene-first): PARP1(142):S4D

Genes: PARP1(142)

Variants: S4D

[Paper-level Aggregated] PMCID: PMC10527017

Evidence Type(s): Functional

Summary: Mutation: V777L | Summary: The HER2V777L mutation alters the invasive phenotype of breast tumor cells and molecular function by enhancing the phosphorylation of key proteins involved in cell cycle regulation. This is indicated by changes in phosphorylation levels and gene expression in breast cancer organoids, as well as the metastatic behavior observed in vitro and in vivo.

Gene→Variant (gene-first): ERBB2(2064):V777L

Genes: ERBB2(2064)

Variants: V777L

[Paper-level Aggregated] PMCID: PMC10390864

Evidence Type(s): Functional

Summary: Mutation: A126T | Summary: The A126T mutation was assessed in a cell-based HDR assay, indicating its influence on RAD51C HR DNA repair activity. It 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: C135Y | Summary: The C135Y mutation was categorized as deleterious in the HDR assay, demonstrating its impact on RAD51C HR DNA repair activity. It introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function. Additionally, it exhibits dramatically reduced 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. It 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: Functional Mutation: D159N | Summary: The D159N mutation was classified as intermediate in the HDR assay, suggesting it alters RAD51C HR DNA repair activity. It 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: 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: G130R | Summary: The G130R variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. It introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function. Additionally, it alters molecular function by causing a significant decrease in RAD51 foci, indicating a disruption in homologous recombination repair.

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: 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: 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: G306R | Summary: The variant p.Gly306Arg (G306R) exhibits altered IC50 values for cisplatin and olaparib, suggesting a functional impact on drug response. It also exhibits partially reduced RAD51 foci formation, indicating it alters molecular function related to DNA damage response.

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. It leads to a significant decrease in RAD51 foci, which suggests a disruption in homologous recombination repair.

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. It introduces a charged or bulky group into a tight hydrophobic pocket, potentially destabilizing the residue 130-140 helical region and influencing RAD51C function. Additionally, it alters molecular function, as evidenced by a decrease in RAD51 foci, suggesting a disruption in homologous recombination repair.

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: P21S | Summary: The P21S variant induces RAD51 foci formation, indicating it alters molecular function related to DNA damage response.

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. It impacts molecular function, leading to a significant decrease in RAD51 foci, indicating a disruption in homologous recombination repair. It also removes a positively charged residue that directly interacts with the negatively charged triphosphate group of ATP, influencing RAD51C function.

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 variant, observed as a homozygous variant in a FANCO patient, displays reduced binding for all complex members, indicating a change in molecular function. It was classified as intermediate in the HDR assay, suggesting it alters RAD51C HR DNA repair activity.

Evidence Type: Functional Mutation: R312W | Summary: The R312W variant was identified as deleterious in the HDR assay, demonstrating its effect on RAD51C HR DNA repair activity. It 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: T132R | Summary: The T132R variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. It affects molecular function, resulting in a significant decrease in RAD51 foci, indicating a disruption in homologous recombination repair. It 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: 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: V140E | Summary: The V140E variant exhibits dramatically reduced RAD51 foci formation, indicating it alters molecular function related to DNA damage response. It 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: G302V | Summary: The G302V variant was confirmed to have functional effects in a human cell line, indicating it alters molecular or biochemical function. It 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. It disrupts a hydrophobic core and may interfere with RAD51C protomer formation, influencing RAD51C 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

Gene→Variant (gene-first): RAD51C(5889):A126T RAD51C(5889):C135Y RAD51C(5889):D109Y RAD51C(5889):D159N RAD51C(5889):G125V RAD51C(5889):G130R RAD51C(5889):G153D RAD51C(5889):G162E RAD51C(5889):G264S RAD51C(5889):G264V RAD51C(5889):G306R RAD51C(5889):K131I RAD51C(5889):L138F RAD51C(5889):L219S RAD51C(5889):P21S RAD51C(5889):R168G RAD51C(5889):R214C RAD51C(5889):R258H RAD51C(5889):R312W RAD51C(5889):T132R RAD51C(5889):T287A RAD51C(5889):V140E RAD51C(5889):G302V RAD51C(5889):T336P

Genes: RAD51C(5889)

Variants: A126T C135Y D109Y D159N G125V G130R G153D G162E G264S G264V G306R K131I L138F L219S P21S R168G R214C R258H R312W T132R T287A V140E G302V T336P

[Paper-level Aggregated] PMCID: PMC10161095

Evidence Type(s): Functional

Summary: 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): PBRM1(55193):lysine-to-methionine

Genes: PBRM1(55193)

Variants: lysine-to-methionine

[Paper-level Aggregated] PMCID: PMC10015977

Evidence Type(s): Functional

Summary: Mutation: K700E | Summary: The K700E mutation is associated with distinct alternative splicing events and altered molecular functions in myelodysplastic syndromes (MDS). Splicing analysis suggests that this variant may influence molecular or biochemical functions related to splicing and mRNA processing.

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): SF3B1(23451):K700E SETBP1(26040):E862K

Genes: SF3B1(23451) SETBP1(26040)

Variants: K700E E862K

[Paper-level Aggregated] PMCID: PMC10011885

Evidence Type(s): Functional

Summary: 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): KDR(3791):A163G SLTM(79811):R106H

Genes: KDR(3791) SLTM(79811)

Variants: A163G R106H

[Paper-level Aggregated] PMCID: PMC9837058

Evidence Type(s): Functional

Summary: Mutation: D915N | Summary: The D915N mutation is described as a kinase dead mutation that does not cause significant changes in protein conformation or membrane binding, indicating its role in altering molecular function without affecting these properties.

Evidence Type: Functional Mutation: N345K | Summary: The N345K mutation in p110alpha is associated with altered membrane binding properties, as evidenced by HDX-MS experiments showing protection in specific regions of the protein when interacting with membranes, indicating a change in molecular function related to membrane association.

Evidence Type: Functional Mutation: E726K | Summary: The E726K mutation alters molecular or biochemical function, particularly in relation to the disengagement of the ABD and p85 from the catalytic core, suggesting conformational changes associated with this mutation.

Evidence Type: Functional Mutation: H1047R | Summary: The H1047R mutation alters molecular function by enhancing membrane binding and increasing basal ATPase activity. It is associated with alterations in molecular or biochemical function, as indicated by the analysis of perturbations in conformation observed in HDX-MS experiments, and shows unique differences in binding interactions upon pY binding.

Evidence Type: Functional Mutation: His1047 | Summary: His1047 is involved in extensive interactions within the kinase domain, indicating that it plays a role in the molecular function of the protein.

Evidence Type: Functional Mutation: Met1043 | Summary: Met1043 is mentioned as a hydrophobic residue that contributes to the structural integrity of the kinase domain, suggesting its role in the molecular function of the protein.

Evidence Type: Functional Mutation: G1049R | Summary: The G1049R mutation alters molecular function by enhancing membrane binding and increasing basal ATPase activity. It shows significantly increased ATPase activity compared to wild type, indicating an alteration in molecular function.

Evidence Type: Functional Mutation: M1043L | Summary: The M1043L mutation alters molecular function by increasing basal ATPase activity with a limited effect on membrane binding. It demonstrates significantly increased ATPase activity compared to wild type and is described in the context of kinase activity.

Evidence Type: Functional Mutation: N1068fs | Summary: The N1068fs mutation alters molecular function by increasing membrane binding without affecting basal ATPase activity and is described in the context of being a kinase dead variant.

Gene→Variant (gene-first): PIK3CA(5290):D915N PIK3CA(5290):N345K PIK3CA(5290):E726K PIK3CA(5290):H1047R PIK3CA(5290):His1047 PIK3CA(5290):Met1043 PIK3CA(5290):G1049R PIK3CA(5290):M1043L PIK3CA(5290):N1068fs

Genes: PIK3CA(5290)

Variants: D915N N345K E726K H1047R His1047 Met1043 G1049R M1043L N1068fs

[Paper-level Aggregated] PMCID: PMC9402235

Evidence Type(s): Functional

Summary: Mutation: c.236A>G; p.Tyr79Cys | Summary: The c.236A>G (p.Tyr79Cys) variant 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. It has been shown to mimic the effects of pVHL deficiency on hypoxic signaling and is associated with mosaicism, suggesting it alters molecular or biochemical function.

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): HIF1A(3091):c.236A>G HIF1A(3091):p.Tyr79Cys NA:c.261_272del (p.Thr88_Pro91del)

Genes: HIF1A(3091) NA

Variants: c.236A>G p.Tyr79Cys c.261_272del (p.Thr88_Pro91del)

[Paper-level Aggregated] PMCID: PMC9398166

Evidence Type(s): Functional

Summary: Mutation: I1171N/S/T | Summary: The I1171N/S/T mutations are described in the context of their impact on the potency of TPX-0131, indicating that these mutations alter the molecular function related to drug response.

Gene→Variant (gene-first): NA:I1171N/S/T

Genes: NA

Variants: I1171N/S/T

[Paper-level Aggregated] PMCID: PMC8881279

Evidence Type(s): Functional

Summary: Mutation: E401G | Summary: The ERBB2 E401G variant alters molecular function by enhancing C-terminal phosphorylation, stabilizing the dimer interface of the HER2-EGFR complex, and activating the MAPK pathway, contributing to changes in proliferative and invasive capacities of cancer cells. It is associated with increased phosphorylation of HER2 and ERK, and does not contribute to the formation of disulfide-linked dimers.

Evidence Type: Functional Mutation: S310F | Summary: The ERBB2 S310F variant alters molecular function by enhancing C-terminal phosphorylation, stabilizing the dimer interface of the HER2-EGFR complex, and activating the MAPK pathway, leading to a significantly higher proliferation rate in cancer cells. It does not show increases in HER2 dimers.

Evidence Type: Functional Mutation: E321G | Summary: The ERBB2 E321G variant alters molecular function by forming disulfide-linked dimers and is involved in activation mechanisms related to dimer formation and C-terminal phosphorylation.

Evidence Type: Functional Mutation: D845A | Summary: The ERBB2 D845A variant is described as a kinase domain inactivating variant and is part of the evaluation of functional properties related to activation mechanisms.

Gene→Variant (gene-first): FANCC(2176):E401G ERBB2(2064):S310F TP53(7157):E321G ERBB2(2064):D845A

Genes: FANCC(2176) ERBB2(2064) TP53(7157)

Variants: E401G S310F E321G D845A

[Paper-level Aggregated] PMCID: PMC8700411

Evidence Type(s): Functional

Summary: 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. The preclinical characterization of an EGFR Exon 20 Insertion Mutant with a G770 equivalence indicates that this variant alters molecular or biochemical function.

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. Additionally, this mutation shows sensitivity to mobocertinib and poziotinib, suggesting functional alterations in response to these therapies.

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): EGFR(1956):G770 EGFR(1956):V769dupASV EGFR(1956):Y764insFQEA

Genes: EGFR(1956)

Variants: G770 V769dupASV Y764insFQEA

[Paper-level Aggregated] PMCID: PMC8688876

Evidence Type(s): Functional

Summary: 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, nucleotide exchange, and distinct vulnerabilities to the enzyme. It is also linked to changes in molecular function, particularly in relation to GAP-mediated hydrolysis and GTP-binding domain activity.

Evidence Type: Functional Mutation: G13 | Summary: The G13 mutation exhibits higher induction with higher variance and is linked to changes in biochemical properties that affect RAF affinity and may influence downstream signaling mechanisms. It is also associated with alterations in molecular function.

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. It is part of the broader distribution of KRAS hotspot variants and is implicated in functional differences related to GTP hydrolysis and signaling pathways.

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. Its RAF affinity profile indicates a change in molecular function.

Evidence Type: Functional Mutation: A146T | Summary: The A146T variant is associated with increased GTP binding and 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: The A146V mutation is associated with alterations in local stability and may modulate local unfolding, indicating a change in molecular function. It is also predicted to have an intermediate decrease in RAF affinity.

Evidence Type: Functional Mutation: A59T | Summary: The A59T variant has a distinct profile among the mutants, indicating a potential alteration in molecular function. It is predicted to have an intermediate decrease in RAF affinity.

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 and is associated with comparable effects to G12S, implicating it in altering molecular function related to GAP-mediated hydrolysis.

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. It is discussed in the context of conflicting reports regarding its effects, suggesting it may alter molecular function.

Evidence Type: Functional Mutation: G12S | Summary: The G12S variant is indicated to have comparable effects to G12A/R and is involved in altering molecular function related to GAP-mediated hydrolysis. It is predicted to have a decreased RAF affinity.

Evidence Type: Functional Mutation: G13C | Summary: The G13C variant is part of a group of variants that relate to local stability and may affect local unfolding, suggesting a functional impact. It is also predicted to have RAF affinity comparable to wild-type, indicating no significant alteration in molecular function.

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. It is also indicated to have a significant effect on GAP-mediated hydrolysis and is predicted to have an intermediate decrease in RAF affinity.

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. It is noted to have comparable effects to G13D and Q61H, indicating a potential alteration in molecular function.

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. 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 behaves like wild-type KRAS, indicating a potential alteration in molecular function. Its RAF affinity profile suggests it alters molecular function in a manner similar to other variants.

Evidence Type: Functional Mutation: Q22K | Summary: The Q22K variant is associated with increased GTP binding and shows a similar RAF affinity profile to other variants, suggesting an alteration in molecular function.

Evidence Type: Functional Mutation: L19F | Summary: The L19F variant shows similarities with hotspot variants, suggesting functional relevance. It is compared to G13D and Q61H, indicating a potential alteration in molecular function and is predicted to have RAF affinity comparable to wild-type.

Evidence Type: Functional Mutation: Q61H | Summary: The Q61H variant is associated with increased GTP binding and is mentioned in relation to its effects on GAP-mediated hydrolysis, suggesting it may alter molecular function. It shows relatively smaller changes in RAF affinity, suggesting a minor 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: Q61R | Summary: The Q61R variant shows a distinct RAF affinity profile, indicating a change in molecular function and is predicted to have RAF affinity comparable to wild-type, indicating no significant alteration in molecular function.

Gene→Variant (gene-first): KRAS(3845):G12 KRAS(3845):G13 KRAS(3845):Q61 KRAS(3845):G12V KRAS(3845):A146T HRAS(3265):A146V HRAS(3265):A59T KRAS(3845):G12A/R KRAS(3845):G12D KRAS(3845):G12S KRAS(3845):G13C HRAS(3265):G13V KRAS(3845):K117N ZHX2(22882):T74 KRAS(3845):R164Q KRAS(3845):Q22K KRAS(3845):L19F KRAS(3845):Q61H KRAS(3845):Q61L/P NRAS(4893):Q61R

Genes: KRAS(3845) HRAS(3265) ZHX2(22882) NRAS(4893)

Variants: G12 G13 Q61 G12V A146T A146V A59T G12A/R G12D G12S G13C G13V K117N T74 R164Q Q22K L19F Q61H Q61L/P Q61R

[Paper-level Aggregated] PMCID: PMC8040738

Evidence Type(s): Functional

Summary: Mutation: p.T599dup | Summary: The BRAF p.T599dup mutation is likely to alter molecular or biochemical function, as it is associated with a specific tumor type and was detected through deep, targeted sequencing of tumor DNA.

Gene→Variant (gene-first): BRAF(673):p.T599dup

Genes: BRAF(673)

Variants: p.T599dup

[Paragraph-level] PMCID: PMC8040738 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: p.T599dup BRAF | Summary: The p.T599dup BRAF variant is associated with tumor development or progression, as indicated by its presence in tumor-extracted DNA from the patient's resection. Evidence Type: Functional | Mutation: p.T599dup BRAF | Summary: The p.T599dup BRAF variant alters molecular or biochemical function, as it was detected through deep, targeted sequencing of tumor DNA.

Gene→Variant (gene-first): NA:p.T599dup BRAF

Genes: NA

Variants: p.T599dup BRAF

[Paragraph-level] PMCID: PMC8040738 Section: RESULTS PassageIndex: 2

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: p.T599dup | Summary: The BRAF p.T599dup mutation was identified in a low-grade glioma, indicating its contribution to tumor development or progression. Evidence Type: Functional | Mutation: p.T599dup | Summary: The BRAF p.T599dup mutation is likely to alter molecular or biochemical function, as it is associated with a specific tumor type.

Gene→Variant (gene-first): 673:p.T599dup

Genes: 673

Variants: p.T599dup

[Paper-level Aggregated] PMCID: PMC8033310

Evidence Type(s): Functional

Summary: Mutation: E545K | Summary: The PIK3CA E545K mutation alters cell viability and apoptosis in TNBC cell lines, indicating a change in molecular function related to cell proliferation and survival. It also downregulates Caspase 3 and upregulates Xiap in tumor tissues, affecting apoptosis.

Gene→Variant (gene-first): PIK3CA(5290):E545K

Genes: PIK3CA(5290)

Variants: E545K

[Paragraph-level] PMCID: PMC8033310 Section: RESULTS PassageIndex: 6

Evidence Type(s): Predictive, Oncogenic, Functional

Summary: Evidence Type: Predictive | Mutation: E545K | Summary: The PIK3CA E545K mutation is associated with induced resistance to chemotherapy in TNBC cells, suggesting a correlation with treatment response. Evidence Type: Oncogenic | Mutation: E545K | Summary: The PIK3CA E545K mutation contributes to tumor development and progression, as indicated by the increased tumor volume in experimental models. Evidence Type: Functional | Mutation: E545K | Summary: The PIK3CA E545K mutation alters molecular function by downregulating Caspase 3 and upregulating Xiap in tumor tissues, affecting apoptosis.

Gene→Variant (gene-first): 5290:E545K

Genes: 5290

Variants: E545K

[Paragraph-level] PMCID: PMC8033310 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: E545K | Summary: The PIK3CAE545K mutation was shown to alter cell viability and apoptosis in TNBC cell lines, indicating a change in molecular function related to cell proliferation and survival. Evidence Type: Oncogenic | Mutation: E545K | Summary: The PIK3CAE545K mutation contributes to tumor development by enhancing the aggressiveness and migratory phenotype of TNBC cells.

Gene→Variant (gene-first): 5290:E545K

Genes: 5290

Variants: E545K

[Paper-level Aggregated] PMCID: PMC8008494

Evidence Type(s): Functional

Summary: Mutation: 2619 from Trp to Gly | Summary: Variants that change residue 2619 from Trp to Gly, Ser, or Cys all resulted in loss of function, indicating a critical role for this residue in molecular function.

Evidence Type: Functional Mutation: 2723 from Asp to Asn | Summary: Variants that change residue 2723 from Asp to Asn, His, Tyr, Ala, Gly, and Val consistently resulted in loss of function, suggesting a negatively charged amino acid is required at this position.

Evidence Type: Functional Mutation: Leu3180 | Summary: Differential effects on function were observed for two alterations in residue Leu3180, where a Pro substitution resulted in loss of function but an Arg substitution resulted in a functional protein.

Evidence Type: Functional Mutation: p.Gly2508Ser | Summary: The variant p.Gly2508Ser is associated with loss of function, indicating its critical role in the molecular function of the protein.

Evidence Type: Functional Mutation: p.Gly2508Arg | Summary: The variant p.Gly2508Arg is associated with loss of function, indicating its critical role in the molecular function of the protein.

Evidence Type: Functional Mutation: p.Ala2603Ser | Summary: The variant p.Ala2603Ser is associated with loss of function, indicating its critical role in the molecular function of the protein.

Evidence Type: Functional Mutation: p.Arg2625Lys | Summary: The variant p.Arg2625Lys is associated with loss of function, indicating its critical role in the molecular function of the protein.

Evidence Type: Functional Mutation: p.Ile2627Val | Summary: The variant p.Ile2627Val is associated with loss of function, indicating its critical role in the molecular function of the protein.

Evidence Type: Functional Mutation: p.Asn3124His | Summary: The variant p.Asn3124His is associated with loss of function, indicating its critical role in the molecular function of the protein.

Evidence Type: Functional Mutation: c.8723T>G | Summary: The variant c.8723T>G (p.Val2908Gly) was evaluated in a functional study and demonstrated sensitivity to multiple drugs, indicating an alteration in molecular function.

Evidence Type: Functional Mutation: c.8905G>A | Summary: The variant c.8905G>A (p.Val2969Met) was also assessed in a functional study and showed consistent sensitivity to various drugs, reflecting a change in molecular function.

Gene→Variant (gene-first): NA:2619 from Trp to Gly BRCA2(675):2723 from Asp to Asn NA:Leu3180 BRCA2(675):p.Gly2508Ser APRT(353):p.Gly2508Arg BRCA2(675):p.Ala2603Ser BRCA2(675):p.Arg2625Lys BRCA2(675):p.Ile2627Val BRCA2(675):p.Asn3124His BRCA2(675):c.8723T>G BRCA2(675):c.8905G>A

Genes: NA BRCA2(675) APRT(353)

Variants: 2619 from Trp to Gly 2723 from Asp to Asn Leu3180 p.Gly2508Ser p.Gly2508Arg p.Ala2603Ser p.Arg2625Lys p.Ile2627Val p.Asn3124His c.8723T>G c.8905G>A

[Paper-level Aggregated] PMCID: PMC7820803

Evidence Type(s): Functional

Summary: Mutation: p.Ala636Pro | Summary: The p.Ala636Pro variant is associated with a destabilizing effect on MSH2 protein expression and alters the molecular function of the MMR machinery. It restores 6-TG sensitivity in a functional assay and is linked to a significant depletion of deleterious scores, indicating alterations in molecular or biochemical function.

Gene→Variant (gene-first): MSH2(4436):p.Ala636Pro

Genes: MSH2(4436)

Variants: p.Ala636Pro

[Paper-level Aggregated] PMCID: PMC7785563

Evidence Type(s): Functional

Summary: 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): NA:MSH6

Genes: NA

Variants: MSH6

[Paper-level Aggregated] PMCID: PMC7612475

Evidence Type(s): Functional

Summary: Mutation: K700E | Summary: The SF3B1 K700E mutation alters molecular function by compromising homologous recombination efficiency, inducing unscheduled R-loop formation, and causing replication fork stalling and degradation. It impacts the resolution of Rad51 foci, decreases sister chromatid exchanges, and affects replication fork restart following a transient replication block, leading to increased basal DNA damage and impaired DNA repair processes.

Evidence Type: Functional Mutation: D210N | Summary: The D210N substitution in RNaseH1 alters its ability to resolve R-loops, leading to their accumulation, which is assessed through fluorescence microscopy.

Gene→Variant (gene-first): SF3B1(23451):K700E RNASEH1(246243):D210N

Genes: SF3B1(23451) RNASEH1(246243)

Variants: K700E D210N

[Paper-level Aggregated] PMCID: PMC7612117

Evidence Type(s): Functional

Summary: Mutation: p.L1363P | Summary: The Brca1 p.L1363P variant alters molecular or biochemical function by disrupting the interaction with PALB2, impairing homologous recombination repair (HRR), and leading to defects in RAD51 foci formation in response to gamma-radiation. It has been shown to cause general growth defects in embryos and is functionally important as it compromises BRCA1-mediated HRR.

Evidence Type: Functional Mutation: p.L1407P | Summary: The p.L1407P variant disrupts the interaction of BRCA1 with PALB2 and is predicted to disable the alpha-helical structure of the coiled-coil domain, indicating a functional alteration. It is analyzed in the context of its potential phenocopy of p.L1363P, suggesting it may also affect molecular interactions and functions related to BRCA1.

Gene→Variant (gene-first): TP53BP1(7158):p.L1363P BRCA1(672):p.L1407P

Genes: TP53BP1(7158) BRCA1(672)

Variants: p.L1363P p.L1407P

[Paper-level Aggregated] PMCID: PMC7545690

Evidence Type(s): Functional

Summary: Mutation: rs3786362 | Summary: The rs3786362 variant is associated with altered expression levels of the TYMS gene, suggesting a functional impact on molecular or biochemical activity in colorectal cancer (CRC) tissues compared to normal tissues.

Gene→Variant (gene-first): TYMS(7298):rs3786362

Genes: TYMS(7298)

Variants: rs3786362

[Paragraph-level] PMCID: PMC7545690 Section: ABSTRACT PassageIndex: 3

Evidence Type(s): Prognostic, Functional

Summary: Evidence Type: Prognostic | Mutation: rs3786362 | Summary: The G allele of the rs3786362 variant in the TYMS gene is significantly associated with progression-free survival (PFS) and overall survival (OS), indicating its potential role as a prognostic marker in cancer outcomes. Evidence Type: Functional | Mutation: rs3786362 | Summary: The rs3786362 variant is associated with altered expression levels of the TYMS gene, suggesting a functional impact on molecular or biochemical activity in colorectal cancer (CRC) tissues compared to normal tissues.

Gene→Variant (gene-first): 7298:rs3786362

Genes: 7298

Variants: rs3786362

[Paper-level Aggregated] PMCID: PMC7294133

Evidence Type(s): Functional

Summary: Mutation: V871I | Summary: The EPHB4-V871I variant does not impair EPHB4 expression at the mRNA and protein levels, but alters molecular function related to cellular proliferation and migration in neuroblastoma (NB) cell lines. It is associated with increased propagation rates, enhanced migration properties in wound-healing experiments, and a higher number of colonies formed in soft agar assays compared to wild type and empty vector controls. Additionally, the variant increases the expression of downstream target genes and enhances phosphorylation of the ERK1-2 pathway, indicating a significant alteration in molecular or biochemical processes.

Gene→Variant (gene-first): EPHB4(2050):V871I

Genes: EPHB4(2050)

Variants: V871I

[Paragraph-level] PMCID: PMC7294133 Section: ABSTRACT PassageIndex: 2

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

Summary: Evidence Type: Oncogenic | Mutation: V871I | Summary: The V871I variant in the EPHB4 gene contributes to tumor development and progression in neuroblastoma by increasing proliferation, migration, and invasion properties in cancer cell lines. Evidence Type: Functional | Mutation: V871I | Summary: The V871I variant alters molecular function by affecting the phosphorylation of the ERK1-2 pathway and influencing the expression of target genes related to cancer progression. Evidence Type: Prognostic | Mutation: V871I | Summary: Higher expression of EPHB4, associated with the V871I variant, correlates with advanced disease stages and poor overall survival in neuroblastoma patients. Evidence Type: Predictive | Mutation: V871I | Summary: The use of EPHB4 inhibitors, which target the effects of the V871I variant, suggests potential therapeutic strategies for neuroblastoma patients.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

[Paper-level Aggregated] PMCID: PMC7211323

Evidence Type(s): Functional

Summary: Mutation: c.285delA | Summary: The mutation c.285delA results in no detectable protein band, indicating that it alters the molecular function of the ACVR2A gene product, likely leading to degradation through nonsense-mediated decay.

Evidence Type: Functional Mutation: 1310AA | Summary: The mutation 1310AA is associated with the production of truncated ACVR2A protein, suggesting that it alters the molecular function of the ACVR2A gene product.

Gene→Variant (gene-first): ACVR2A(92):c.285delA ACVR2A(92):1310AA

Genes: ACVR2A(92)

Variants: c.285delA 1310AA

[Paragraph-level] PMCID: PMC7211323 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: c.285delA | Summary: The mutation c.285delA results in no detectable protein band, indicating that it alters the molecular function of the ACVR2A gene product, likely leading to degradation through nonsense-mediated decay. Evidence Type: Functional | Mutation: 1310AA | Summary: The mutation 1310AA is associated with the production of truncated ACVR2A protein, suggesting that it alters the molecular function of the ACVR2A gene product.

Gene→Variant (gene-first): 92:1310AA 92:c.285delA

Genes: 92

Variants: 1310AA c.285delA

[Paper-level Aggregated] PMCID: PMC7190743

Evidence Type(s): Functional

Summary: Mutation: C124S | Summary: The C124S variant is characterized as catalytically inactive for both protein and lipid phosphatase functions, showing complete loss of function (LoF) indistinguishable from GFP controls in terms of PSD95 density. It alters molecular function by raising pAKT/AKT levels, consistent with a dominant negative phenotype, and is involved in genetic interactions that alter PI3P metabolism, indicating a significant alteration in molecular function.

Evidence Type: Functional Mutation: G129E | Summary: The G129E variant is described as a lipid phosphatase-dead variant and alters molecular function by raising pAKT/AKT levels, consistent with a dominant negative phenotype. It exhibited eclosion significantly faster than the empty vector control, suggesting a functional change in its activity.

Evidence Type: Functional Mutation: Y138L | Summary: Y138L is identified as a protein phosphatase-dead variant, indicating a change in the molecular function of the PTEN protein.

Evidence Type: Functional Mutation: N117S | Summary: The N117S variant slowed the developmental rate further than the wild-type, indicating a functional alteration in its role.

Evidence Type: Functional Mutation: Q298E | Summary: The Q298E variant also slowed the developmental rate further than the wild-type, suggesting a functional change in its activity.

Evidence Type: Functional Mutation: A79T | Summary: The A79T variant exhibited a gain-of-function (GoF) phenotype in axonal growth and altered PSD95 density and dendrite length, indicating a change in molecular function. It retained wild-type-like function in the context of chemotaxis assays in C. elegans.

Evidence Type: Functional Mutation: I101T | Summary: The I101T variant, along with C124S, increased soma size more than GFP, suggesting a change in molecular function related to neuronal growth.

Evidence Type: Functional Mutation: G132D | Summary: The G132D variant exhibited stronger negative chemotaxis than daf-18 mutants and increased soma size more than GFP, indicating a functional alteration associated with neuronal growth.

Evidence Type: Functional Mutation: D268E | Summary: The D268E variant showed partial loss of function (LoF) in the chemotaxis assays in daf-18 mutant worms and appeared wild-type-like in all measures of growth and synaptogenesis, suggesting it does not alter molecular function significantly.

Evidence Type: Functional Mutation: T167N | Summary: The T167N variant showed partial loss of function (LoF) in the chemotaxis assays in daf-18 mutant worms.

Evidence Type: Functional Mutation: Y176C | Summary: The Y176C variant showed partial loss of function (LoF) in the chemotaxis assays in daf-18 mutant worms.

Evidence Type: Functional Mutation: H93Y | Summary: The H93Y variant is associated with altered molecular function, specifically reduced protein stability compared to wild-type PTEN.

Evidence Type: Functional Mutation: P354Q | Summary: The P354Q variant retained wild-type-like function in the context of chemotaxis assays in C. elegans and does not show significant differences in protein stability compared to wild-type PTEN, indicating it may not alter molecular function.

Evidence Type: Functional Mutation: R130L | Summary: The R130L variant alters molecular function by exhibiting a change in stability between parental and PTEN-KO cells, suggesting its interaction with endogenous PTEN has minimal influence and does not show significant differences in protein stability compared to wild-type PTEN.

Evidence Type: Functional Mutation: R14G | Summary: The R14G variant does not show significant differences in protein stability compared to wild-type PTEN, indicating it may not alter molecular function.

Evidence Type: Functional Mutation: R15S | Summary: The R15S variant does not show significant differences in protein stability compared to wild-type PTEN, indicating it may not alter molecular function.

Evidence Type: Functional Mutation: T78A | Summary: The T78A variant does not show significant differences in protein stability compared to wild-type PTEN, indicating it may not alter molecular function.

Evidence Type: Functional Mutation: A126D | Summary: The A126D variant alters molecular function by exhibiting a change in stability between parental and PTEN-KO cells, suggesting its interaction with endogenous PTEN has minimal influence.

Evidence Type: Functional Mutation: A126P | Summary: The A126P variant alters molecular function by exhibiting a change in stability between parental and PTEN-KO cells, indicating its interaction with endogenous PTEN has minimal influence.

Evidence Type: Functional Mutation: H123Q | Summary: The H123Q variant alters molecular function by exhibiting a change in stability between parental and PTEN-KO cells, suggesting its interaction with endogenous PTEN has minimal influence.

Evidence Type: Functional Mutation: P38H | Summary: The P38H variant alters molecular function by exhibiting a change in stability between parental and PTEN-KO cells, indicating its interaction with endogenous PTEN has minimal influence.

Evidence Type: Functional Mutation: R130Q | Summary: The R130Q variant alters molecular function by exhibiting a change in stability between parental and PTEN-KO cells, indicating its interaction with endogenous PTEN has minimal influence.

Gene→Variant (gene-first): PTEN(5728):C124S PTEN(5728):G129E PTEN(5728):Y138L PTEN(5728):N117S PTEN(5728):Q298E PTEN(5728):A79T PTEN(5728):I101T PTEN(5728):G132D PTEN(5728):D268E PTEN(5728):T167N PTEN(5728):Y176C PTEN(5728):H93Y PTEN(5728):P354Q PTEN(5728):R130L PTEN(5728):R14G PTEN(5728):R15S PTEN(5728):T78A PTEN(5728):A126D PTEN(5728):A126P PTEN(5728):H123Q PTEN(5728):P38H PTEN(5728):R130Q

Genes: PTEN(5728)

Variants: C124S G129E Y138L N117S Q298E A79T I101T G132D D268E T167N Y176C H93Y P354Q R130L R14G R15S T78A A126D A126P H123Q P38H R130Q

[Paper-level Aggregated] PMCID: PMC7182441

Evidence Type(s): Functional

Summary: Mutation: S6 | Summary: The variant S6 is involved in the molecular function related to mTOR signaling and autophagy in response to amino acid starvation, as indicated by the effects of alpha-MT on the phosphorylation status of S6 kinase in LS174T cells.

Gene→Variant (gene-first): RPS6KB1(6198):S6

Genes: RPS6KB1(6198)

Variants: S6

[Paragraph-level] PMCID: PMC7182441 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: S6 | Summary: The passage discusses the effects of alpha-MT on the phosphorylation status of S6 kinase in LS174T cells, indicating that the variant S6 is involved in the molecular function related to mTOR signaling and autophagy in response to amino acid starvation.

Gene→Variant (gene-first): 6198:S6

Genes: 6198

Variants: S6

[Paper-level Aggregated] PMCID: PMC7099049

Evidence Type(s): Functional

Summary: Mutation: rs16879870 | Summary: The genotype of rs16879870 is significantly associated with the expression of the gene GJB7 in cancer tissues, with allele A linked to increased mRNA expression levels, indicating a potential functional impact on gene expression.

Evidence Type: Functional Mutation: rs854936 | Summary: The genotype of rs854936 is significantly associated with the expression of the gene RTN4R in cancer tissues, with allele C linked to increased mRNA levels, suggesting a functional role in gene expression.

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

Genes: NA

Variants: rs16879870 rs854936

[Paper-level Aggregated] PMCID: PMC7064492

Evidence Type(s): Functional

Summary: Mutation: p.K57N | Summary: The p.K57N variant in MAP2K1 alters molecular function related to endothelial cell behavior, suggesting alterations in molecular or biochemical function and contributing to the pathophysiology of arteriovenous malformation (AVM). Its presence is enriched in endothelial cells compared to non-endothelial cells.

Gene→Variant (gene-first): MAP2K1(5604):p.K57N

Genes: MAP2K1(5604)

Variants: p.K57N

[Paragraph-level] PMCID: PMC7064492 Section: RESULTS PassageIndex: 2

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: p.K57N | Summary: The MAP2K1 (p.K57N) mutation was found in the tissue adjacent to the cartilage in patients with auricular AVM, indicating its potential role in tumor development or progression. Evidence Type: Functional | Mutation: p.K57N | Summary: The presence of the MAP2K1 (p.K57N) mutation suggests alterations in molecular or biochemical function, as indicated by its enrichment in endothelial cells compared to non-endothelial cells.

Gene→Variant (gene-first): 5604:p.K57N

Genes: 5604

Variants: p.K57N

[Paragraph-level] PMCID: PMC7064492 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: p.K57N | Summary: The MAP2K1 mutation p.K57N is associated with the development of arteriovenous malformation (AVM) through its presence in endothelial cells, indicating its role in tumor progression. Evidence Type: Functional | Mutation: p.K57N | Summary: The p.K57N variant in MAP2K1 alters the molecular function related to endothelial cell behavior, contributing to the pathophysiology of AVM.

Gene→Variant (gene-first): 5604:p.K57N

Genes: 5604

Variants: p.K57N

[Paper-level Aggregated] PMCID: PMC6843359

Evidence Type(s): Functional

Summary: Mutation: S310F | Summary: The S310F mutation alters the reactivity and binding properties of the HER2 protein, affecting its interactions with specific antibodies and forming heterodimers with EGFR. This indicates a significant change in molecular and biochemical function, as evidenced by analyses in bladder cancer cell lines, including expression confirmation through immunoprecipitation and fluorescence intensity measurements.

Gene→Variant (gene-first): ERBB2(2064):S310F

Genes: ERBB2(2064)

Variants: S310F

[Paper-level Aggregated] PMCID: PMC6791388

Evidence Type(s): Functional

Summary: Mutation: S133; Ser133; Serine 133 | Summary: The mutation at Serine 133 is associated with altered phosphorylation of CREB, indicating a change in molecular function that may contribute to MEKi resistance in leukemic cells.

Gene→Variant (gene-first): TP53(7157):S133 TP53(7157):Ser133 TP53(7157):Serine 133

Genes: TP53(7157)

Variants: S133 Ser133 Serine 133

[Paper-level Aggregated] PMCID: PMC6627713

Evidence Type(s): Functional

Summary: 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.

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: 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): KRAS(3845):c.183A>T KRAS(3845):p.Gln61His MAP2K1(5604):c.169A>G MAP2K1(5604):p.Lys57Glu NF1(4763):c.638_639insA NF1(4763):c.5101A>T

Genes: KRAS(3845) MAP2K1(5604) NF1(4763)

Variants: c.183A>T p.Gln61His c.169A>G p.Lys57Glu c.638_639insA c.5101A>T

[Paper-level Aggregated] PMCID: PMC6594036

Evidence Type(s): Functional

Summary: 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): KRAS(3845):Arg918Cys TEK(7010):Tyr897Cys

Genes: KRAS(3845) TEK(7010)

Variants: Arg918Cys Tyr897Cys

[Paper-level Aggregated] PMCID: PMC6547725

Evidence Type(s): Functional

Summary: Mutation: p.Q22K | Summary: The p.Q22K mutation is associated with increased GTP loading, indicating an alteration in molecular or biochemical function.

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. Additionally, insertions in Gln61 indicate alterations in molecular function related to GTP hydrolysis.

Evidence Type: Functional Mutation: p.Q61L | Summary: The functional consequences of the p.Q61L mutation in relation to RAS signaling indicate that it is a classic pathogenic missense mutation that may alter molecular function.

Evidence Type: Functional Mutation: p.G12V | Summary: The p.G12V variant alters the intrinsic dissociation rate of the nucleotide, shows reduced intrinsic GTP hydrolysis rates compared to wild type, and induces phosphorylation of ERK and AKT, indicating significant changes in molecular function and its role in RAS signaling pathways.

Gene→Variant (gene-first): KRAS(3845):p.Q22K RASA1(5921):Gln61 NRAS(4893):p.Q61L KRAS(3845):p.G12V

Genes: KRAS(3845) RASA1(5921) NRAS(4893)

Variants: p.Q22K Gln61 p.Q61L p.G12V

[Paper-level Aggregated] PMCID: PMC6547681

Evidence Type(s): Functional

Summary: Mutation: G101V | Summary: The G101V mutation alters the molecular interaction of BCL-2 with venetoclax, affecting drug binding and contributing to resistance. It changes the interactions within the P2 pocket, impacting the positioning of venetoclax in relation to the BCL-2 structure. Additionally, it affects 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: 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. It also alters the conformation and binding affinity of the BCL-2 protein, impacting its interaction with venetoclax. Furthermore, 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: E152A | Summary: The E152A mutation restores venetoclax binding, indicating a functional alteration that can counteract the resistance caused by the G101V mutation. It maintains comparable binding to wild-type BCL-2 and restores high affinity for venetoclax when combined with G101V. The E152A double mutant also shows altered binding affinity to S55746, indicating a functional impact on molecular interactions.

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. It exhibits a binding affinity to venetoclax that is comparable to wild-type BCL-2, indicating a functional role in drug interaction.

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): BCL2(596):G101V BCL2(596):E152 BCL2(596):E152A BCL2(596):G101A BCL2(596):F104L BCL2(596):F104

Genes: BCL2(596)

Variants: G101V E152 E152A G101A F104L F104

[Paper-level Aggregated] PMCID: PMC6478919

Evidence Type(s): Functional

Summary: Mutation: T > C | Summary: The T > C variant at location 21 of BCL2 alters its RNA secondary structure and is associated with significant increases in BCL2 expression levels and mRNA stability, indicating a change in molecular function. It also correlates with increased BCL2 transcript levels and may affect spatial expression patterns.

Evidence Type: Functional Mutation: C > T | Summary: The C > T change at location 21 in BCL2 alters molecular function by stabilizing the BCL2 RNA secondary structure in vitro and correlates with increased BCL2 transcript levels.

Evidence Type: Functional Mutation: + 21 T > C | Summary: The + 21 T > C variant is evaluated for its structural consequences and is hypothesized to lead to a more stable transcript, resulting in increased BCL2 protein levels, indicating a change in molecular function.

Evidence Type: Functional Mutation: + 23 C > T | Summary: The + 23 C > T variant shows an insignificant change in structure and does not significantly alter molecular function, although it was included in studies evaluating BCL2 expression.

Evidence Type: Functional Mutation: 21 T > C | Summary: The 21 T > C variant in BCL2 is associated with a significant increase in BCL2 mRNA levels and leads to a more stable transcript, indicating an alteration in molecular function.

Gene→Variant (gene-first): BCL2(596):T > C BCL2(596):C > T BCL2(596):+ 21 T > C POTEF(728378):+ 23 C > T BCL2(596):21 T > C

Genes: BCL2(596) POTEF(728378)

Variants: T > C C > T + 21 T > C + 23 C > T 21 T > C

[Paragraph-level] PMCID: PMC6478919 Section: RESULTS PassageIndex: 26

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: 21 T > C | Summary: The 21 T > C mutation in BCL2 was studied for its impact on spatial expression patterns, indicating that it alters molecular localization, although it did not show differences in localization compared to the reference form.

Gene→Variant (gene-first): 596:21 T > C

Genes: 596

Variants: 21 T > C

[Paragraph-level] PMCID: PMC6478919 Section: RESULTS PassageIndex: 22

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: 21 T > C | Summary: The variant 21 T > C in the BCL2 sequence correlates with increased sensitivity to paclitaxel, suggesting a potential predictive role in therapy response. Evidence Type: Functional | Mutation: 21 T > C | Summary: The 21 T > C variant leads to a more stable BCL2 transcript, which may result in higher protein levels, indicating an alteration in molecular function.

Gene→Variant (gene-first): 596:21 T > C

Genes: 596

Variants: 21 T > C

[Paragraph-level] PMCID: PMC6478919 Section: RESULTS PassageIndex: 20

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: 21 T > C | Summary: The 21 T > C variant in BCL2 is associated with a significant increase in BCL2 mRNA levels, indicating that this mutation alters the transcriptional activity of the gene. Evidence Type: Functional | Mutation: C instead of a T | Summary: The presence of a C instead of a T at position 21 in BCL2 correlates with an increase in BCL2 transcript levels, suggesting a functional impact on gene expression.

Gene→Variant (gene-first): 596:21 T > C 596:C instead of a T

Genes: 596

Variants: 21 T > C C instead of a T

[Paragraph-level] PMCID: PMC6478919 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: + 21 T > C | Summary: The + 21 T > C substitution is hypothesized to lead to a more stable transcript, resulting in increased BCL2 protein levels, indicating a change in molecular function. Evidence Type: Oncogenic | Mutation: + 21 T > C | Summary: The increase in BCL2 protein levels associated with the + 21 T > C mutation suggests a contribution to tumor development or progression in ovarian cancer patients.

Gene→Variant (gene-first): 596:+ 21 T > C 596:C instead of a T

Genes: 596

Variants: + 21 T > C C instead of a T

[Paragraph-level] PMCID: PMC6478919 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: T to C | Summary: The mutation T to C at location 21 alters molecular function by increasing protein levels in vitro.

Gene→Variant (gene-first): 596:T to C

Genes: 596

Variants: T to C

[Paragraph-level] PMCID: PMC6478919 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: T > C | Summary: The T > C mutation is associated with altered molecular function, specifically increasing the stability of BCL2 mRNA transcripts.

Gene→Variant (gene-first): 596:T > C

Genes: 596

Variants: T > C

[Paragraph-level] PMCID: PMC6478919 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: T > C | Summary: The T > C variant was shown to significantly increase BCL2 expression levels, indicating an alteration in molecular function related to transcript stability. Evidence Type: Functional | Mutation: +21 C | Summary: The +21 C variant was part of the experimental validation that assessed its effect on BCL2 expression, suggesting a role in altering molecular function. Evidence Type: Functional | Mutation: +23 C > T | Summary: The +23 C > T variant was included in the study to evaluate its impact on BCL2 expression, indicating a potential alteration in molecular function.

Gene→Variant (gene-first): 596:+21 C 596:+21 T 728378:+23 C > T 596:T > C

Genes: 596 728378

Variants: +21 C +21 T +23 C > T T > C

[Paragraph-level] PMCID: PMC6478919 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: C to T | Summary: The C to T mutation at location 21 in BCL2 alters the molecular function by stabilizing the BCL2 RNA secondary structure in vitro.

Gene→Variant (gene-first): 596:C to T

Genes: 596

Variants: C to T

[Paragraph-level] PMCID: PMC6478919 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: C > T | Summary: The C > T change in BCL2 is assessed for its potential to alter mRNA structural ensemble, indicating a possible functional impact on molecular behavior. Evidence Type: Functional | Mutation: T > C | Summary: The T > C variant at position 21 shows a significant structural change as indicated by a lower p-value, suggesting it alters molecular function. Evidence Type: Functional | Mutation: + 21 T > C | Summary: The + 21 T > C variant is compared with adjacent variations and is evaluated for its structural consequences, indicating a potential functional alteration. Evidence Type: Functional | Mutation: + 23 C > T | Summary: The + 23 C > T variant is tested as a control and shows an insignificant change in structure, indicating it does not alter molecular function significantly.

Gene→Variant (gene-first): 596:+ 21 T > C 728378:+ 23 C > T 596:C > T 596:T > C 596:T at position 21

Genes: 596 728378

Variants: + 21 T > C + 23 C > T C > T T > C T at position 21

[Paragraph-level] PMCID: PMC6478919 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: T >C | Summary: The T >C variant at location 21 of BCL2 alters its RNA secondary structure, indicating a change in molecular function.

Gene→Variant (gene-first): 596:T >C

Genes: 596

Variants: T >C

[Paper-level Aggregated] PMCID: PMC6368247

Evidence Type(s): Functional

Summary: Mutation: Q75E | Summary: The Q75E mutation in ESR1 is mentioned in relation to changes in dominant mutations and sub-clonal selection, suggesting it may have functional implications, although it is not recognized as a cause of resistance.

Evidence Type: Functional Mutation: Q257X | Summary: The Q257X mutation is likely to result in abrogated Rb function due to the introduction of a stop codon, affecting the molecular function of the RB1 protein.

Gene→Variant (gene-first): ESR1(2099):Q75E RB1(5925):Q257X

Genes: ESR1(2099) RB1(5925)

Variants: Q75E Q257X

[Paragraph-level] PMCID: PMC6368247 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: Q257X | Summary: The Q257X mutation in the RB1 gene is associated with the development of resistance to palbociclib and fulvestrant treatment, indicating its role in tumor progression. Evidence Type: Functional | Mutation: Q257X | Summary: The Q257X mutation is likely to result in abrogated Rb function due to the introduction of a stop codon, affecting the molecular function of the RB1 protein.

Gene→Variant (gene-first): 5925:Q257X

Genes: 5925

Variants: Q257X

[Paragraph-level] PMCID: PMC6368247 Section: RESULTS PassageIndex: 6

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: p.K569E | Summary: The p.K569E mutation in FGFR2 is described as an activating mutation that contributes to tumor development, particularly in the context of resistance to treatment with palbociclib plus fulvestrant. Evidence Type: Functional | Mutation: Q75E | Summary: The Q75E mutation in ESR1 is mentioned in relation to changes in dominant mutations and sub-clonal selection, suggesting it may have functional implications, although it is not recognized as a cause of resistance. Evidence Type: Oncogenic | Mutation: D538G | Summary: The D538G mutation in ESR1 was negatively selected during treatment, indicating its role in tumor progression and response to therapy, thus supporting its oncogenic potential.

Gene→Variant (gene-first): 2263:D538G 2099:Q75E 2263:p.K569E

Genes: 2263 2099

Variants: D538G Q75E p.K569E

[Paper-level Aggregated] PMCID: PMC5873857

Evidence Type(s): Functional

Summary: Mutation: c.159_173del | Summary: The c.159_173del variant alters the molecular function of the MAP2K1 gene, which is implicated in the RAS/MAPK signaling pathway, and is predicted to affect the integrity of helix A, indicating a biochemical impact relevant to the clinical phenotype observed in patients with arteriovenous malformations (AVMs).

Evidence Type: Functional Mutation: E62del | Summary: The deletion of residues 58-62 (E62del) is predicted to affect the integrity of helix A, indicating an alteration in molecular function.

Evidence Type: Functional Mutation: K57 | Summary: K57 is identified as a critical amino acid involved in a hydrogen bond interaction, suggesting its role in the molecular function of the protein.

Evidence Type: Functional Mutation: c.173_187del | Summary: The deletion c.173_187del is predicted to affect the integrity of helix A, indicating an alteration in molecular function.

Evidence Type: Functional Mutation: p.[K57N] | Summary: The missense variant p.[K57N] is associated with critical interactions in the protein structure, suggesting an alteration in molecular function.

Gene→Variant (gene-first): MAP2K1(5604):c.159_173del MAP2K1(5604):E62del NA:K57 MAP2K1(5604):c.173_187del MAP2K1(5604):p.[K57N]

Genes: MAP2K1(5604) NA

Variants: c.159_173del E62del K57 c.173_187del p.[K57N]

[Paragraph-level] PMCID: PMC5873857 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: E62del | Summary: The deletion of residues 58-62 (E62del) is predicted to affect the integrity of helix A, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: K57 | Summary: K57 is identified as a critical amino acid involved in a hydrogen bond interaction, suggesting its role in the molecular function of the protein. Evidence Type: Functional | Mutation: c.159_173del | Summary: The novel deletion c.159_173del is predicted to affect the integrity of helix A, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: c.173_187del | Summary: The deletion c.173_187del is predicted to affect the integrity of helix A, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: p.[K57N] | Summary: The missense variant p.[K57N] is associated with critical interactions in the protein structure, suggesting an alteration in molecular function.

Gene→Variant (gene-first): 5604:E62del NA:K57 5604:c.159_173del 5604:c.173_187del 5604:p.[K57N]

Genes: 5604 NA

Variants: E62del K57 c.159_173del c.173_187del p.[K57N]

[Paragraph-level] PMCID: PMC5873857 Section: RESULTS PassageIndex: 2

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: c.159_173del | Summary: The variant c.159_173del is part of a cluster of pathogenic variants identified in MAP2K1, contributing to the development of arteriovenous malformations (AVMs) and indicating its role in tumor progression within the RAS/MAPK signaling pathway. Evidence Type: Functional | Mutation: c.159_173del | Summary: The c.159_173del variant alters the molecular function of the MAP2K1 gene, which is implicated in the RAS/MAPK signaling pathway, suggesting a biochemical impact relevant to the clinical phenotype observed in patients with AVMs.

Gene→Variant (gene-first): 5604:c.159_173del

Genes: 5604

Variants: c.159_173del

[Paper-level Aggregated] PMCID: PMC5822176

Evidence Type(s): Functional

Summary: Mutation: K27M | Summary: The presence of diffuse H3 K27M immunostaining suggests that this mutation alters molecular function related to histone modification, indicating its role in tumor development and progression.

Gene→Variant (gene-first): IDH1(3417):K27M

Genes: IDH1(3417)

Variants: K27M

[Paper-level Aggregated] PMCID: PMC5820258

Evidence Type(s): Functional

Summary: 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): TP53(7157):p.W110*

Genes: TP53(7157)

Variants: p.W110*

[Paper-level Aggregated] PMCID: PMC5762309

Evidence Type(s): Functional

Summary: Mutation: V559D | Summary: The V559D mutation alters the molecular function of the KIT protein, affecting cell proliferation, auto-phosphorylation, and phosphorylation at specific sites. It demonstrates changes in molecular function related to treatment response and is evidenced by its selectivity and efficacy in biochemical assays and signaling pathways.

Evidence Type: Functional Mutation: L576P | Summary: The L576P mutation alters molecular or biochemical function, as indicated by its mention in binding assays.

Evidence Type: Functional Mutation: A829P | Summary: The A829P mutation alters molecular or biochemical function, as suggested by its discussion in binding assays.

Evidence Type: Functional

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

Genes: KIT(3815)

Variants: V559D L576P A829P

[Paper-level Aggregated] PMCID: PMC5629366

Evidence Type(s): Functional

Summary: Mutation: R132H | Summary: The R132H mutation alters the histone methylation phenotype in AML cells, demonstrating a change in molecular function related to histone trimethylation levels.

Gene→Variant (gene-first): IDH1(3417):R132H

Genes: IDH1(3417)

Variants: R132H

[Paragraph-level] PMCID: PMC5629366 Section: RESULTS PassageIndex: 17

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: R132H | Summary: The R132H mutation in IDH1 is associated with sensitivity to the treatment with BAY1436032, indicating a correlation with therapeutic response in AML cells. Evidence Type: Functional | Mutation: R132H | Summary: The R132H mutation alters the histone methylation phenotype in AML cells, demonstrating a change in molecular function related to histone trimethylation levels.

Gene→Variant (gene-first): 3417:R132H

Genes: 3417

Variants: R132H

[Paper-level Aggregated] PMCID: PMC5615879

Evidence Type(s): Functional

Summary: Mutation: p.K558delinsBP | Summary: The mutation p.K558delinsBP (c.1673_1674insTCC) indicates an alteration in molecular or biochemical function due to the insertion of nucleotides.

Evidence Type: Functional Mutation: Ala-Tyr | Summary: The duplication of Ala-Tyr at codons 502-503 suggests an alteration in molecular function due to the mutation.

Evidence Type: Functional Mutation: p.Y503_F504insTY | Summary: The insertion of p.Y503_F504insTY indicates a change in the molecular or biochemical function associated with the mutation.

Gene→Variant (gene-first): KIT(3815):p.K558delinsBP KIT(3815):Ala-Tyr KIT(3815):p.Y503_F504insTY

Genes: KIT(3815)

Variants: p.K558delinsBP Ala-Tyr p.Y503_F504insTY

[Paragraph-level] PMCID: PMC5615879 Section: RESULTS PassageIndex: 16

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: c.1504_1509 dup GCCTAT | Summary: The mutation c.1504_1509 dup GCCTAT is associated with tumor development in cases of small intestine tumors, indicating its role in oncogenesis. Evidence Type: Functional | Mutation: Ala-Tyr | Summary: The duplication of Ala-Tyr at codons 502-503 suggests an alteration in molecular function due to the mutation. Evidence Type: Oncogenic | Mutation: c.1509_1510insACCTAT | Summary: The insertion mutation c.1509_1510insACCTAT is noted in a case of duodenal GIST, contributing to tumor progression. Evidence Type: Functional | Mutation: p.Y503_F504insTY | Summary: The insertion of p.Y503_F504insTY indicates a change in the molecular or biochemical function associated with the mutation.

Gene→Variant (gene-first): 3815:Ala-Tyr 3815:c.1504_1509 dup GCCTAT 3815:c.1509_1510insACCTAT 3815:p.Y503_F504insTY

Genes: 3815

Variants: Ala-Tyr c.1504_1509 dup GCCTAT c.1509_1510insACCTAT p.Y503_F504insTY

[Paragraph-level] PMCID: PMC5615879 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: p.K558delinsBP | Summary: The mutation p.K558delinsBP (c.1673_1674insTCC) indicates an alteration in molecular or biochemical function due to the insertion of nucleotides.

Gene→Variant (gene-first): 3815:K580dup 3815:c.1673_1674insTCC 3815:c.1731_1742dupTTATGATCACAA 3815:p.K558delinsBP

Genes: 3815

Variants: K580dup c.1673_1674insTCC c.1731_1742dupTTATGATCACAA p.K558delinsBP

[Paper-level Aggregated] PMCID: PMC5613053

Evidence Type(s): Functional

Summary: Mutation: F691 | Summary: The F691 position is noted for its hydrophobic interaction with gilteritinib, indicating a functional alteration in the molecular interaction with the drug.

Gene→Variant (gene-first): FLT3(2322):F691

Genes: FLT3(2322)

Variants: F691

[Paragraph-level] PMCID: PMC5613053 Section: RESULTS PassageIndex: 12

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: D835Y | Summary: The mutation D835Y is associated with the response to gilteritinib, a type 1 FLT3 inhibitor, indicating its predictive value for therapy. Evidence Type: Predictive | Mutation: D835 | Summary: The mutation D835 is implicated in the response to gilteritinib, suggesting its role in predicting treatment outcomes. Evidence Type: Functional | Mutation: F691 | Summary: The F691 position is noted for its hydrophobic interaction with gilteritinib, indicating a functional alteration in the molecular interaction with the drug.

Gene→Variant (gene-first): 2322:D835 2322:D835Y 2322:F691

Genes: 2322

Variants: D835 D835Y F691

[Paper-level Aggregated] PMCID: PMC5509015

Evidence Type(s): Functional

Summary: 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): VHL(7428):Trp53 deletion

Genes: VHL(7428)

Variants: Trp53 deletion

[Paper-level Aggregated] PMCID: PMC5491373

Evidence Type(s): Functional

Summary: Mutation: L320S | Summary: The L320S mutation alters the molecular function of the PTEN protein by decreasing its stability, affecting its localization, and inhibiting its ability to suppress AKT phosphorylation. It also creates a new potential phosphorylation site, impacts PTEN's conformation, and alters its interaction with the membrane-bound regulatory interface, leading to increased ubiquitination.

Evidence Type: Functional Mutation: T277A | Summary: The T277A mutation alters the molecular function of the PTEN protein by decreasing its stability, impacting its localization, and inhibiting its ability to suppress AKT phosphorylation. It affects PTEN's conformation, alters its ubiquitination, and modifies the interaction between the membrane-binding regulatory interface and the C-terminal tail of PTEN.

Evidence Type: Functional Mutation: K13 | Summary: The K13 mutation is involved in blocking ubiquitination, which affects PTEN stability and its degradation process, suggesting a functional alteration.

Evidence Type: Functional Mutation: K13R | Summary: The K13R mutation blocks ubiquitination at K13, impacting PTEN stability and its biochemical function.

Evidence Type: Functional Mutation: C124S | Summary: The C124S mutation stabilizes PTEN by presumably inhibiting its enzymatic activity, indicating a change in molecular function.

Evidence Type: Functional Mutation: T366 | Summary: Phosphorylation at T366 is shown to destabilize the PTEN protein, suggesting a functional impact on its molecular behavior.

Evidence Type: Functional Mutation: S370 | Summary: Phosphorylation at S370 contributes to the destabilization of the PTEN protein, indicating a change in its molecular function.

Evidence Type: Functional Mutation: T366A | Summary: The T366A mutation is part of constructs that were tested for stability, indicating its role in altering the molecular function of PTEN.

Evidence Type: Functional Mutation: S370A | Summary: The S370A mutation is included in constructs that failed to stabilize PTEN, suggesting an impact on its molecular function.

Evidence Type: Functional Mutation: F273 | Summary: The F273 mutation is suggested to alter the molecular function of PTEN by affecting its conformation and localization.

Evidence Type: Functional Mutation: F273A | Summary: The F273A mutation shows altered inhibition on nuclear accumulation and membrane localization, indicating a change in molecular function.

Evidence Type: Functional Mutation: F273L | Summary: The F273L mutation is involved in restoring the localization of PTEN, suggesting it impacts the molecular function of the protein.

Evidence Type: Functional Mutation: L320 | Summary: The L320 mutation is implicated in maintaining PTEN conformation necessary for its localization, indicating a functional role.

Evidence Type: Functional Mutation: L320A | Summary: The introduction of L320A into PTENA4 does not affect the strong inhibition of membrane and nuclear localization, indicating a functional role in PTEN's behavior.

Evidence Type: Functional Mutation: L320D | Summary: The phospho-mimetic mutation L320D does not show instabilities similar to those seen in PTENL320S, suggesting a functional difference in protein behavior.

Evidence Type: Functional Mutation: L320E | Summary: Similar to L320D, the phospho-mimetic mutation L320E does not exhibit instabilities like PTENL320S, indicating its functional impact on PTEN.

Evidence Type: Functional Mutation: T319 | Summary: The T319 residue is involved in phosphorylation by ROCK, suggesting it plays a role in the molecular function of PTEN.

Evidence Type: Functional Mutation: T319A | Summary: The T319A mutation does not enhance protein stability, indicating an alteration in the molecular function of PTEN.

Evidence Type: Functional Mutation: T321 | Summary: The T321 residue is involved in phosphorylation by ROCK, suggesting it plays a role in the molecular function of PTEN.

Evidence Type: Functional Mutation: T321A | Summary: The T321A mutation does not enhance protein stability, indicating an alteration in the molecular function of PTEN.

Evidence Type: Functional Mutation: Lys48 | Summary: The mutation Lys48 is involved in the formation of polyubiquitin chains, and its alteration affects the molecular function related to nuclear localization of the PTENL320S variant.

Evidence Type: Functional Mutation: K48R | Summary: The K48R mutation alters the molecular function of ubiquitin, affecting the localization and abundance of PTENL320S-GFP, indicating its role in nuclear accumulation and degradation processes.

Gene→Variant (gene-first): NEDD4(4734):L320S PTEN(5728):T277A GAPDH(2597):K13 GAPDH(2597):K13R PTEN(5728):C124S PTEN(5728):T366 PTEN(5728):S370 PTEN(5728):T366A PTEN(5728):S370A PIK3R1(5295):F273 PIK3R1(5295):F273A PIK3R1(5295):F273L NEDD4(4734):L320 NEDD4(4734):L320A NEDD4(4734):L320D NEDD4(4734):L320E PTEN(5728):T319 PTEN(5728):T319A PTEN(5728):T321 PTEN(5728):T321A PTEN(5728):Lys48 PTEN(5728):K48R

Genes: NEDD4(4734) PTEN(5728) GAPDH(2597) PIK3R1(5295)

Variants: L320S T277A K13 K13R C124S T366 S370 T366A S370A F273 F273A F273L L320 L320A L320D L320E T319 T319A T321 T321A Lys48 K48R

[Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 31

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K13 | Summary: The substitution of K13 to arginine alters the molecular function of PTEN, blocking its redistribution to the nucleus.

Gene→Variant (gene-first): 2597:K13

Genes: 2597

Variants: K13

[Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 30

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K48R | Summary: The K48R mutation alters the molecular function of ubiquitin, affecting the localization and abundance of PTENL320S-GFP, indicating its role in nuclear accumulation and degradation processes.

Gene→Variant (gene-first): 5728:K48R

Genes: 5728

Variants: K48R

[Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 29

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: Lys48 | Summary: The mutation Lys48 is involved in the formation of polyubiquitin chains, and its alteration affects the molecular function related to nuclear localization of the PTENL320S variant.

Gene→Variant (gene-first): 5728:Lys48

Genes: 5728

Variants: Lys48

[Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 26

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: T277A | Summary: The T277A mutation alters the ability of the membrane-binding regulatory interface to interact with the C-terminal tail of PTEN, indicating a change in molecular function. Evidence Type: Functional | Mutation: L320S | Summary: The L320S mutation also affects the interaction between the membrane-binding regulatory interface and the C-terminal tail of PTEN, suggesting a modification in molecular function.

Gene→Variant (gene-first): 4734:L320S 5728:T277A

Genes: 4734 5728

Variants: L320S T277A

[Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 25

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L320S | Summary: The L320S mutation alters molecular function by inhibiting the interaction between the membrane-bound regulatory interface and the C-terminus. Evidence Type: Functional | Mutation: T277A | Summary: The T277A mutation alters molecular function by inhibiting the interaction between the membrane-bound regulatory interface and the C-terminus.

Gene→Variant (gene-first): 4734:L320S

Genes: 4734

Variants: L320S

[Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 24

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: T277A | Summary: The T277A mutation alters the ubiquitination of PTEN, indicating a change in molecular function related to protein stability. Evidence Type: Functional | Mutation: L320S | Summary: The L320S mutation also affects the ubiquitination of PTEN, suggesting a modification in molecular function that impacts protein stability.

Gene→Variant (gene-first): 4734:L320S 5728:T277A

Genes: 4734 5728

Variants: L320S T277A

[Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 23

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L320S | Summary: The L320S mutation alters the protein conformation and folding of PTEN, as evidenced by its susceptibility to trypsin digestion compared to wild-type PTEN. Evidence Type: Functional | Mutation: T277A | Summary: The T277A mutation affects the protein conformation and folding of PTEN, demonstrated by its lower half-lives during trypsin digestion relative to wild-type PTEN.

Gene→Variant (gene-first): 4734:L320S 5728:T277A

Genes: 4734 5728

Variants: L320S T277A

[Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 22

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: F273 | Summary: The F273 mutation is suggested to alter the molecular function of PTEN by affecting its conformation and localization. Evidence Type: Functional | Mutation: F273A | Summary: The F273A mutation shows altered inhibition on nuclear accumulation and membrane localization, indicating a change in molecular function. Evidence Type: Functional | Mutation: F273L | Summary: The F273L mutation is involved in restoring the localization of PTEN, suggesting it impacts the molecular function of the protein. Evidence Type: Functional | Mutation: L320 | Summary: The L320 mutation is implicated in maintaining PTEN conformation necessary for its localization, indicating a functional role. Evidence Type: Functional | Mutation: L320S | Summary: The L320S mutation shows altered inhibition similar to F273A, suggesting it affects the molecular function of PTEN. Evidence Type: Functional | Mutation: L320F | Summary: The L320F mutation is involved in restoring PTEN localization, indicating a change in its molecular function.

Gene→Variant (gene-first): 5295:F273 5295:F273A 5295:F273L 4734:L320 4734:L320F 4734:L320S

Genes: 5295 4734

Variants: F273 F273A F273L L320 L320F L320S

[Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 21

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: T277A | Summary: The T277A mutation alters the molecular conformation of PTEN, promoting its ubiquitination. Evidence Type: Functional | Mutation: L320S | Summary: The L320S mutation also affects the conformation of PTEN, leading to increased ubiquitination.

Gene→Variant (gene-first): 4734:L320S 5728:T277A

Genes: 4734 5728

Variants: L320S T277A

[Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 20

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L320S | Summary: The L320S mutation affects phosphorylation at other sites on PTEN, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: T319 | Summary: The T319 residue is involved in phosphorylation by ROCK, suggesting it plays a role in the molecular function of PTEN. Evidence Type: Functional | Mutation: T319A | Summary: The T319A mutation does not enhance protein stability, indicating an alteration in the molecular function of PTEN. Evidence Type: Functional | Mutation: T321 | Summary: The T321 residue is involved in phosphorylation by ROCK, suggesting it plays a role in the molecular function of PTEN. Evidence Type: Functional | Mutation: T321A | Summary: The T321A mutation does not enhance protein stability, indicating an alteration in the molecular function of PTEN.

Gene→Variant (gene-first): 4734:L320S 5728:T319 5728:T319A 5728:T321 5728:T321A

Genes: 4734 5728

Variants: L320S T319 T319A T321 T321A

[Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 19

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L320S | Summary: The substitution of L320 to S alters the molecular function of PTEN by creating a new potential phosphorylation site, which affects its stability and localization. Evidence Type: Functional | Mutation: L320A | Summary: The introduction of L320A into PTENA4 does not affect the strong inhibition of membrane and nuclear localization, indicating a functional role in PTEN's behavior. Evidence Type: Functional | Mutation: L320D | Summary: The phospho-mimetic mutation L320D does not show instabilities similar to those seen in PTENL320S, suggesting a functional difference in protein behavior. Evidence Type: Functional | Mutation: L320E | Summary: Similar to L320D, the phospho-mimetic mutation L320E does not exhibit instabilities like PTENL320S, indicating its functional impact on PTEN.

Gene→Variant (gene-first): 4734:L320 4734:L320A 4734:L320D 4734:L320E 4734:L320S

Genes: 4734

Variants: L320 L320A L320D L320E L320S

[Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: T277A | Summary: The T277A mutation alters PTEN's ability to localize to the plasma membrane, resulting in its retention in the cytosol and affecting its function in reducing AKT phosphorylation. Evidence Type: Functional | Mutation: L320S | Summary: The L320S mutation similarly inhibits PTEN's membrane localization, leading to its accumulation in the cytosol and potentially impacting its role in tumor suppression. Evidence Type: Functional | Mutation: K13R | Summary: The K13R mutation is involved in the context of PTEN localization studies, but specific functional impacts are not detailed in the passage.

Gene→Variant (gene-first): 2597:K13R 4734:L320S 5728:T277A

Genes: 2597 4734 5728

Variants: K13R L320S T277A

[Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L320S | Summary: The L320S mutation alters the molecular function by blocking PTEN membrane and nuclear localization. Evidence Type: Functional | Mutation: T277A | Summary: The T277A mutation alters the molecular function by blocking PTEN membrane and nuclear localization.

Gene→Variant (gene-first): 4734:L320S 5728:T277A

Genes: 4734 5728

Variants: L320S T277A

[Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L320S | Summary: The L320S mutation is associated with altered stability of the PTEN protein, indicating a change in molecular function. Evidence Type: Functional | Mutation: T366 | Summary: Phosphorylation at T366 is shown to destabilize the PTEN protein, suggesting a functional impact on its molecular behavior. Evidence Type: Functional | Mutation: S370 | Summary: Phosphorylation at S370 contributes to the destabilization of the PTEN protein, indicating a change in its molecular function. Evidence Type: Functional | Mutation: T366A | Summary: The T366A mutation is part of constructs that were tested for stability, indicating its role in altering the molecular function of PTEN. Evidence Type: Functional | Mutation: S370A | Summary: The S370A mutation is included in constructs that failed to stabilize PTEN, suggesting an impact on its molecular function.

Gene→Variant (gene-first): 4734:L320S 5728:S370 5728:S370A 5728:T366 5728:T366A

Genes: 4734 5728

Variants: L320S S370 S370A T366 T366A

[Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L320S | Summary: The L320S mutation decreases the stability of PTEN and alters its interactions with the plasma membrane, indicating a change in molecular function. Evidence Type: Functional | Mutation: K13 | Summary: The K13 mutation is involved in blocking ubiquitination, which affects PTEN stability and its degradation process, suggesting a functional alteration. Evidence Type: Functional | Mutation: K13R | Summary: The K13R mutation blocks ubiquitination at K13, impacting PTEN stability and its biochemical function. Evidence Type: Functional | Mutation: C124S | Summary: The C124S mutation stabilizes PTEN by presumably inhibiting its enzymatic activity, indicating a change in molecular function.

Gene→Variant (gene-first): 5728:C124S 2597:K13 2597:K13R 4734:L320S

Genes: 5728 2597 4734

Variants: C124S K13 K13R L320S

[Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L320S | Summary: The PTENL320S variant shows decreased activity to suppress AKT phosphorylation, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: T277A | Summary: The PTENT277A variant also demonstrates decreased activity to suppress AKT phosphorylation, suggesting a change in molecular function.

Gene→Variant (gene-first): 4734:L320S 5728:T277A

Genes: 4734 5728

Variants: L320S T277A

[Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L320S | Summary: The L320S mutation was tested for its effect on enzymatic activity, showing lipid phosphatase activity indistinguishable from wild-type PTEN, indicating it does not alter molecular function. Evidence Type: Functional | Mutation: T277A | Summary: The T277A mutation was also tested for its effect on enzymatic activity, demonstrating lipid phosphatase activity similar to wild-type PTEN, suggesting it does not alter molecular function.

Gene→Variant (gene-first): 4734:L320S 5728:T277A

Genes: 4734 5728

Variants: L320S T277A

[Paragraph-level] PMCID: PMC5491373 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L320S | Summary: The L320S mutation alters the molecular function of the PTEN protein, as it is associated with decreased steady state levels and affects PTEN localization. Evidence Type: Functional | Mutation: T277A | Summary: The T277A mutation also alters the molecular function of the PTEN protein, leading to decreased steady state levels and impacting PTEN localization.

Gene→Variant (gene-first): 4734:L320S 5728:T277A

Genes: 4734 5728

Variants: L320S T277A

[Paper-level Aggregated] PMCID: PMC5481739

Evidence Type(s): Functional

Summary: Mutation: V716F | Summary: The DNMT3A-V716F mutation is predicted to affect methyltransferase activity, indicating a change in molecular function associated with this variant.

Gene→Variant (gene-first): DNMT3A(1788):V716F

Genes: DNMT3A(1788)

Variants: V716F

[Paper-level Aggregated] PMCID: PMC5111006

Evidence Type(s): Functional

Summary: Mutation: p.R474 | Summary: The variant p.R474 of CHEK2 shows high conservation in homologs, suggesting potential functional significance. It is involved in forming a salt bridge 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, leading to protein instability and poor activation in response to DNA damage. This alteration affects the molecular function of CHK2, indicating its functional importance.

Evidence Type: Functional Mutation: p.R210 | Summary: The mutation p.R210 is not well conserved and does not significantly affect the function or structure of the protein, particularly in its interaction with the immunoglobulin Fc fragment.

Evidence Type: Functional Mutation: p.R210Q | Summary: The mutation p.R210Q is not likely to affect the function and structure of the protein, indicating a focus on its molecular function.

Gene→Variant (gene-first): CHEK2(11200):p.R474 CHEK2(11200):p.R474C FCGRT(2217):p.R210 FCGRT(2217):p.R210Q

Genes: CHEK2(11200) FCGRT(2217)

Variants: p.R474 p.R474C p.R210 p.R210Q

[Paper-level Aggregated] PMCID: PMC5083195

Evidence Type(s): Functional

Summary: Mutation: rs1122269 | Summary: The variant rs1122269 showed negative correlations with the expression of CDH4 in a cis-manner, indicating it may alter molecular function related to gene expression. It also affects CDH4 expression levels in lymphoblastoid cell lines after exposure to gemcitabine, demonstrating a functional impact on molecular expression.

Evidence Type: Functional Mutation: rs4925193 | Summary: The variant rs4925193 demonstrated negative correlations with the expression of CDH4 in a cis-manner, suggesting it may influence molecular function associated with gene expression.

Gene→Variant (gene-first): CDH4(1002):rs1122269 CDH4(1002):rs4925193

Genes: CDH4(1002)

Variants: rs1122269 rs4925193

[Paragraph-level] PMCID: PMC5083195 Section: RESULTS PassageIndex: 16

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: rs1122269 | Summary: The SNP rs1122269 in the CDH4 gene correlates with the response to gemcitabine treatment, indicating its potential as a predictive biomarker for therapy response. Evidence Type: Functional | Mutation: rs1122269 | Summary: The variant rs1122269 affects CDH4 expression levels in lymphoblastoid cell lines after exposure to gemcitabine, demonstrating a functional impact on molecular expression.

Gene→Variant (gene-first): 1002:rs1122269

Genes: 1002

Variants: rs1122269

[Paragraph-level] PMCID: PMC5083195 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Prognostic

Summary: Evidence Type: Functional | Mutation: rs1122269 | Summary: The variant rs1122269 showed negative correlations with the expression of CDH4 in a cis-manner, indicating it may alter molecular function related to gene expression. Evidence Type: Functional | Mutation: rs4925193 | Summary: The variant rs4925193 also demonstrated negative correlations with the expression of CDH4 in a cis-manner, suggesting it may influence molecular function associated with gene expression. Evidence Type: Prognostic | Mutation: rs1122269 | Summary: The mRNA expression levels of CDH4, associated with variant rs1122269, correlated with overall survival (OS) in pancreatic cancer patients, indicating a potential prognostic role. Evidence Type: Prognostic | Mutation: rs4925193 | Summary: The mRNA expression levels of CDH4, associated with variant rs4925193, correlated with overall survival (OS) in pancreatic cancer patients, suggesting a potential prognostic significance.

Gene→Variant (gene-first): 1002:rs1122269 1002:rs4925193 NA:rs9637468

Genes: 1002 NA

Variants: rs1122269 rs4925193 rs9637468

[Paper-level Aggregated] PMCID: PMC5029699

Evidence Type(s): Functional

Summary: Mutation: K650 | Summary: The K650 mutation alters molecular or biochemical function, with assessments indicating its impact on FGFR3 activity.

Evidence Type: Functional Mutation: K650E | Summary: The K650E mutation significantly increases auto-phosphorylation of FGFR3 KD, alters the conformation of the A-loop, and is associated with altered kinase activity, indicating a change 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: 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: N540K | Summary: The N540K mutation leads to a substantial increase in auto-phosphorylation of FGFR3 KD and is located near the ATP binding pocket, 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 and is located near the ATP binding pocket, suggesting it may alter the molecular function of FGFR3.

Evidence Type: Functional Mutation: I538 | Summary: The I538 mutation is part of the molecular brake in the FGFR3 structure, indicating it may affect molecular or biochemical function.

Evidence Type: Functional Mutation: I538V | Summary: The I538V mutation had a substantial effect on drug binding, indicating an alteration in molecular function.

Evidence Type: Functional Mutation: R669 | Summary: The R669 mutation alters molecular interactions and is associated with cancer, indicating its contribution to tumor development or progression.

Evidence Type: Functional Mutation: R669G | Summary: The R669G mutation is the most activating variant, resulting in increased auto-phosphorylation of FGFR3 KD, alters molecular interactions, and promotes an active conformation, indicating a change in molecular function.

Evidence Type: Functional Mutation: R669Q | Summary: The R669Q mutation results in increased auto-phosphorylation of FGFR3 KD, indicating an alteration in molecular function.

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: 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: Functional Mutation: G637W | Summary: The G637W mutation resulted in kinase inactivation, demonstrating an alteration in molecular function.

Evidence Type: Functional Mutation: G697C | Summary: The G697C mutation alters molecular or biochemical function, although it does not affect kinase activity directly as measured in vitro.

Evidence Type: Functional Mutation: D617G | Summary: The D617G mutation completely abolished kinase activity, indicating that it alters molecular function.

Evidence Type: Functional Mutation: V555 | Summary: The V555 mutation is associated with an increase in kinase activity, indicating an alteration in molecular function.

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: E466K | Summary: The E466K mutation is predicted to reduce protein production or completely inactivate the kinase, indicating a functional alteration.

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): FGFR3(2261):K650 FGFR3(2261):K650E FGFR3(2261):K650N FGFR3(2261):N540 FGFR3(2261):N540K FGFR3(2261):N540S FGFR2(2263):I538 FGFR2(2263):I538V FGFR3(2261):R669 FGFR3(2261):R669G FGFR3(2261):R669Q FGFR1(2260):D641 FGFR1(2260):D641G FGFR1(2260):D641N FGFR1(2260):G637W FGFR3(2261):G697C FGFR3(2261):D617G FGFR3(2261):V555 FGFR3(2261):V555M FGFR2(2263):E466K FGFR1(2260):R675G FGFR1(2260):R675 FGFR3(2261):H650 FGFR2(2263):Y653

Genes: FGFR3(2261) FGFR2(2263) FGFR1(2260)

Variants: K650 K650E K650N N540 N540K N540S I538 I538V R669 R669G R669Q D641 D641G D641N G637W G697C D617G V555 V555M E466K R675G R675 H650 Y653

[Paper-level Aggregated] PMCID: PMC5019182

Evidence Type(s): Functional

Summary: 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.

Gene→Variant (gene-first): PIK3CA(5290):p.Ala1035Thr PIK3CA(5290):p.Ala1035Val

Genes: PIK3CA(5290)

Variants: p.Ala1035Thr p.Ala1035Val

[Paper-level Aggregated] PMCID: PMC5002925

Evidence Type(s): Functional

Summary: 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.

Evidence Type: Functional Mutation: p.L755S | Summary: The ERBB2 p.L755S mutation is described in the context of its biological significance, indicating an alteration in molecular function.

Gene→Variant (gene-first): BRAF(673):p.N581S ERBB2(2064):p.L755S

Genes: BRAF(673) ERBB2(2064)

Variants: p.N581S p.L755S

[Paper-level Aggregated] PMCID: PMC4899144

Evidence Type(s): Functional

Summary: Mutation: Y641F | Summary: The Y641F mutation alters molecular function by affecting global levels of H3K27me3, enzymatic activity, and gene expression regulation in B-cells and melanoma cells. It is associated with a gain-of-function effect, increased apoptotic resistance, and a global redistribution of H3K27me3 marks across the genome. The mutation also alters the expression of numerous transcripts and affects the distribution of H3K27me3 at promoter regions.

Evidence Type: Functional Mutation: Y646F | Summary: The Y646F mutation is described as equivalent to the Y641F mutation, suggesting it alters molecular function, although specific functional data is limited. It affects the molecular function of Ezh2 and exhibits in vitro activity against the JQEZ5 inhibitor, indicating a correlation with treatment response.

Gene→Variant (gene-first): EZH2(2146):Y641F EZH2(2146):Y646F

Genes: EZH2(2146)

Variants: Y641F Y646F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 23

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: Y641F | Summary: The Ezh2Y641F mutation alters the molecular function of the enzyme, leading to a global redistribution of H3K27me3 marks across the genome in melanoma cell lines. Evidence Type: Oncogenic | Mutation: Y641F | Summary: The Ezh2Y641F mutation contributes to tumor development by affecting the epigenetic landscape, as indicated by changes in H3K27me3 distribution in melanoma cell lines.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 22

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: Y641F | Summary: The Ezh2Y641F mutation alters the H3K27me3 signal around the transcription start site and gene body, indicating a change in molecular function related to gene expression regulation. Evidence Type: Oncogenic | Mutation: Y641F | Summary: The Ezh2Y641F mutation is associated with changes in gene expression in B-cells and melanoma cell lines, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 21

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: Y641F | Summary: The Ezh2Y641F mutation alters the distribution of H3K27me3 at promoter regions and affects gene expression, indicating a change in molecular function related to transcription regulation. Evidence Type: Oncogenic | Mutation: Y641F | Summary: The Ezh2Y641F mutation contributes to tumor development by affecting the expression of genes regulated by PRC2, suggesting its role in cancer progression.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: Y641F | Summary: The Ezh2Y641F mutation alters the expression of numerous transcripts in both B-cells and melanoma cells, indicating a change in molecular function associated with this variant. Evidence Type: Oncogenic | Mutation: Y641F | Summary: The Ezh2Y641F mutation is implicated in tumor development as it is expressed in melanoma cell lines derived from tumors, suggesting a role in cancer progression.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 12

Evidence Type(s): Predictive, Oncogenic, Functional

Summary: Evidence Type: Predictive | Mutation: Y641F | Summary: The Y641F mutation in Ezh2 is associated with increased sensitivity to the EZH2 inhibitor JQEZ5, indicating a correlation with treatment response. Evidence Type: Oncogenic | Mutation: Y641F | Summary: The Y641F mutation in Ezh2 is implicated in tumor initiation and maintenance, contributing to tumor development in melanoma. Evidence Type: Functional | Mutation: Y641F | Summary: The Y641F mutation alters the enzymatic activity of Ezh2, as evidenced by the differential response to EZH2 inhibitors in cell lines. Evidence Type: Predictive | Mutation: Y646F | Summary: The Y646F mutation exhibits in vitro activity against the JQEZ5 inhibitor, suggesting a correlation with treatment response. Evidence Type: Oncogenic | Mutation: Y646F | Summary: The Y646F mutation in Ezh2 is involved in tumor development and progression in melanoma. Evidence Type: Functional | Mutation: Y646F | Summary: The Y646F mutation affects the molecular function of Ezh2, as indicated by its response to pharmacological inhibitors.

Gene→Variant (gene-first): 2146:Y641F 2146:Y646F

Genes: 2146

Variants: Y641F Y646F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: Y641F | Summary: The Y641F mutation in EZH2 exhibits altered methylase activity, demonstrating a change in molecular function compared to wild-type EZH2. Evidence Type: Oncogenic | Mutation: Y641F | Summary: The presence of the Y641F mutation contributes to tumorigenesis, as evidenced by the development of splenomegaly and lymphadenopathy in mice harboring this mutation. Evidence Type: Functional | Mutation: Y646 | Summary: The passage suggests that mutations at position Y646 may also affect molecular function, although specific details are not provided.

Gene→Variant (gene-first): 2146:Y641F 2146:Y646 2146:tyrosine to phenylalanine

Genes: 2146

Variants: Y641F Y646 tyrosine to phenylalanine

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: Y641F | Summary: The Ezh2Y641F mutation contributes to tumor development and progression in B-cell lymphomas, as indicated by its role in accelerating lymphoma formation when combined with other genetic alterations. Evidence Type: Functional | Mutation: Y641F | Summary: The Ezh2Y641F variant alters molecular function by affecting the global levels of H3K27me3, which is associated with apoptotic resistance and B-cell transformation.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: Y641F | Summary: The Y641F mutation alters molecular function, as it is associated with a gain-of-function effect, leading to increased H3K27me3 levels in B-cells. Evidence Type: Oncogenic | Mutation: Y641F | Summary: The Y641F mutation is equivalent to a common EZH2 missense mutation found in human cancers, indicating its contribution to tumor development. Evidence Type: Functional | Mutation: Y646F | Summary: The Y646F mutation is described as equivalent to the Y641F mutation, suggesting it also alters molecular function, although specific functional data for Y646F is not detailed in the passage. Evidence Type: Oncogenic | Mutation: Y646F | Summary: The Y646F mutation is noted as one of the most common EZH2 missense mutations in human cancers, indicating its role in tumor development.

Gene→Variant (gene-first): 2146:Y641F 2146:Y646F

Genes: 2146

Variants: Y641F Y646F

[Paper-level Aggregated] PMCID: PMC4868698

Evidence Type(s): Functional

Summary: 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: Functional Mutation: S703I | Summary: The JAK1S703I mutation alters the molecular function by activating the JAK-STAT signaling pathway and driving cell proliferation in vitro, contributing to tumor development by enabling continual proliferation in the absence of IL-3.

Gene→Variant (gene-first): JAK1(3716):E483D JAK1(3716):S703I

Genes: JAK1(3716)

Variants: E483D S703I

[Paragraph-level] PMCID: PMC4868698 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Functional, Predictive, Oncogenic

Summary: Evidence Type: Functional | Mutation: S703I | Summary: The JAK1S703I mutation alters the molecular function by activating the JAK-STAT signaling pathway and driving cell proliferation in vitro. Evidence Type: Predictive | Mutation: S703I | Summary: The JAK1S703I mutation correlates with sensitivity to the JAK1/2 inhibitor ruxolitinib, indicating its potential as a predictive biomarker for therapy response in HCC. Evidence Type: Oncogenic | Mutation: S703I | Summary: The JAK1S703I mutation contributes to tumor development by activating the JAK-STAT signaling pathway, which is associated with cell proliferation in the absence of cytokine stimulation.

Gene→Variant (gene-first): 3716:S703I

Genes: 3716

Variants: S703I

[Paper-level Aggregated] PMCID: PMC4823825

Evidence Type(s): Functional

Summary: Mutation: K27M | Summary: The K27M mutation alters the molecular function of histone proteins, specifically in the context of histone 3 variants, impacting chromatin regulation and contributing to tumorigenesis.

Evidence Type: Functional Mutation: H1047R | Summary: The H1047R mutation affects the catalytic domain of PIK3CA, indicating an alteration in molecular or biochemical function related to the PI3K pathway.

Gene→Variant (gene-first): H3C2(8358):K27M PIK3CA(5290):H1047R

Genes: H3C2(8358) PIK3CA(5290)

Variants: K27M H1047R

[Paragraph-level] PMCID: PMC4823825 Section: RESULTS PassageIndex: 12

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: H1047R | Summary: The PIK3CA H1047R mutation is described as an activating mutation that contributes to tumor development and progression, particularly in high-grade astrocytoma (WHO IV). Evidence Type: Functional | Mutation: H1047R | Summary: The H1047R mutation affects the catalytic domain of PIK3CA, indicating an alteration in molecular or biochemical function related to the PI3K pathway.

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

Genes: 5290

Variants: H1047R

[Paragraph-level] PMCID: PMC4823825 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: K27M | Summary: The K27M mutation is identified as an oncogenic mutation associated with high-grade gliomas (HGG) and is present in a majority of the analyzed DIPG samples, indicating its contribution to tumor development. Evidence Type: Functional | Mutation: K27M | Summary: The K27M mutation alters the molecular function of histone proteins, specifically in the context of histone 3 variants, impacting chromatin regulation and contributing to tumorigenesis.

Gene→Variant (gene-first): 8358:K27M

Genes: 8358

Variants: K27M

[Paper-level Aggregated] PMCID: PMC4823091

Evidence Type(s): Functional

Summary: Mutation: V855A | Summary: The V855A mutation alters the molecular function of the HER3 protein, affecting its phosphorylation levels, growth response, and colony formation ability in various cellular contexts. It enhances the interaction with HER2 and trans-phosphorylation, indicating significant changes in molecular or biochemical function. Additionally, in silico modeling suggests alterations in the kinase domain and carboxyl-terminal end of the HER3 protein.

Evidence Type: Functional Mutation: L858 | Summary: The L858 mutation is part of a conserved sequence motif that stabilizes the inactive position of the alphaC helix, indicating potential functional relevance.

Evidence Type: Functional Mutation: L597V | Summary: The L597V mutation is associated with increased ERK activation, indicating a functional alteration in molecular activity.

Gene→Variant (gene-first): APC(324):V855A EGFR(1956):L858 BRAF(673):L597V

Genes: APC(324) EGFR(1956) BRAF(673)

Variants: V855A L858 L597V

[Paragraph-level] PMCID: PMC4823091 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Predictive, Functional

Summary: Evidence Type: Oncogenic | Mutation: V855A | Summary: The HER3 V855A somatic mutation is implicated in the development and progression of non-small cell lung cancer (NSCLC) and enhances ligand-induced transformation in cell lines, indicating its role in tumor development. Evidence Type: Predictive | Mutation: V855A | Summary: The presence of the HER3 V855A mutation suggests potential sensitivity to HER-targeted inhibitors, indicating its relevance in predicting response to targeted therapies in NSCLC. Evidence Type: Functional | Mutation: V855A | Summary: In silico modeling predicts that the V855A mutation alters the kinase domain and c-terminal end of the HER3 protein, indicating a change in molecular function.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

[Paragraph-level] PMCID: PMC4823091 Section: RESULTS PassageIndex: 26

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: V855A | Summary: The V855A mutation alters the activity of HER3, indicating a change in molecular or biochemical function. Evidence Type: Oncogenic | Mutation: V855A | Summary: The V855A mutation may correlate with a malignant phenotype, suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

[Paragraph-level] PMCID: PMC4823091 Section: RESULTS PassageIndex: 25

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: V855A | Summary: The V855A mutation alters the molecular structure of the wild-type HER3 protein, specifically affecting the kinase domain and the carboxyl-terminal end.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

[Paragraph-level] PMCID: PMC4823091 Section: RESULTS PassageIndex: 24

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: V855A | Summary: The variant V855A is associated with alterations in the molecular or biochemical function of the HER3 protein.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

[Paragraph-level] PMCID: PMC4823091 Section: RESULTS PassageIndex: 22

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: V855A | Summary: The V855A mutation in HER3 is associated with differential response to HER inhibitors, indicating its predictive value for therapy effectiveness. Evidence Type: Functional | Mutation: V855A | Summary: The V855A mutation alters the colony formation ability of HER3 co-transfectants, demonstrating a change in molecular function.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

[Paragraph-level] PMCID: PMC4823091 Section: RESULTS PassageIndex: 19

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: V855A | Summary: The V855A mutation alters the molecular interaction between HER3 and HER2, enhancing their physical interaction, particularly in the presence of NRG1beta. Evidence Type: Oncogenic | Mutation: V855A | Summary: The V855A mutation contributes to tumor development by increasing the activity of HER3 through enhanced interaction with HER2, suggesting a role in cancer progression.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

[Paragraph-level] PMCID: PMC4823091 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: V855A | Summary: The HER3-V855A variant enhances trans-phosphorylation of HER2, indicating an alteration in molecular function related to HER signaling. Evidence Type: Oncogenic | Mutation: V855A | Summary: The HER3-V855A variant contributes to tumor development by enhancing HER2 trans-phosphorylation, which is a key event in cancer signaling pathways.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

[Paragraph-level] PMCID: PMC4823091 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: V855A | Summary: The V855A mutation alters the molecular function of HER3, as it affects the phosphorylation levels of HER3 and its downstream targets in response to NRG1beta treatment. Evidence Type: Oncogenic | Mutation: V855A | Summary: The V855A mutation contributes to tumor development or progression, as it is associated with transforming activity that requires a competent HER2 receptor.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

[Paragraph-level] PMCID: PMC4823091 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: V855A | Summary: The HER3-V855A mutation alters the molecular function of Ba/F3 cells, affecting their growth response and colony formation in the presence of TGFalpha. Evidence Type: Oncogenic | Mutation: V855A | Summary: The HER3-V855A mutation is implicated in tumor development as it demonstrates a robust growth response in a cellular model, indicating its potential role in oncogenic processes.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

[Paragraph-level] PMCID: PMC4823091 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: V855A | Summary: The HER3-V855A variant alters the colony formation ability, resulting in significantly larger colony sizes compared to wild-type HER3, indicating a change in molecular function. Evidence Type: Oncogenic | Mutation: V855A | Summary: The HER3-V855A variant contributes to tumor development or progression as evidenced by its enhanced colony formation capabilities in the presence of NRG1beta treatment.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

[Paragraph-level] PMCID: PMC4823091 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: V855A | Summary: The HER3-V855A mutation alters the growth response of Ba/F3 cells in the presence of NRG1beta, indicating a change in molecular function related to HER3 activation. Evidence Type: Oncogenic | Mutation: V855A | Summary: The HER3-V855A mutation contributes to tumor development by promoting IL-3-independent growth in the presence of specific ligands, suggesting its role in oncogenic processes.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

[Paragraph-level] PMCID: PMC4823091 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: V855A | Summary: The HER3-V855A mutation was studied in a Ba/F3 model system to determine its functional impact, indicating that it alters molecular or biochemical function. Evidence Type: Oncogenic | Mutation: V855A | Summary: The HER3-V855A mutation is described as a contributor to oncogenic transformation and tumorigenesis, particularly in combination with HER2, suggesting its role in tumor development.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

[Paragraph-level] PMCID: PMC4823091 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: V855A | Summary: The V855A mutation is suggested to have a functional effect due to its position in a conserved sequence motif that may affect protein kinase activity. Evidence Type: Functional | Mutation: L858 | Summary: The L858 mutation is part of a conserved sequence motif that stabilizes the inactive position of the alphaC helix, indicating potential functional relevance. Evidence Type: Oncogenic | Mutation: L597V | Summary: The L597V mutation is classified as an intermediate kinase active variant that significantly increases BRAF activity, contributing to tumor development. Evidence Type: Functional | Mutation: L597V | Summary: The L597V mutation is associated with increased ERK activation, indicating a functional alteration in molecular activity.

Gene→Variant (gene-first): 673:L597V 1956:L858 1956:L858R 324:V855 324:V855A

Genes: 673 1956 324

Variants: L597V L858 L858R V855 V855A

[Paragraph-level] PMCID: PMC4823091 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L858R | Summary: The L858R mutation is mentioned in the context of its homology with the HER3-V855A mutation, suggesting a potential alteration in molecular or biochemical function. Evidence Type: Functional | Mutation: V855A | Summary: The V855A mutation is mentioned in the context of its homology with the EGFR-L858R mutation, indicating a potential alteration in molecular or biochemical function.

Gene→Variant (gene-first): 1956:L858R 324:V855A

Genes: 1956 324

Variants: L858R V855A

[Paragraph-level] PMCID: PMC4823091 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: T-to-C | Summary: The T-to-C mutation in the HER3 gene is identified as a somatic variant that contributes to tumor development, as it was detected in the tumor sample but not in the patient's peripheral blood DNA. Evidence Type: Oncogenic | Mutation: V855A | Summary: The V855A mutation in the HER3 gene is a somatic variant that plays a role in tumor progression, as indicated by its presence in the tumor sample. Evidence Type: Functional | Mutation: p. Val855Ala | Summary: The p. Val855Ala mutation alters the molecular function of the HER3 protein, as it involves a substitution of valine to alanine at codon 855, which is part of the activation loop.

Gene→Variant (gene-first): 2065:T-to-C 324:V855A 324:p. Val855Ala 324:valine (GTG) to alanine (GCG) at codon 855

Genes: 2065 324

Variants: T-to-C V855A p. Val855Ala valine (GTG) to alanine (GCG) at codon 855

[Paper-level Aggregated] PMCID: PMC4748120

Evidence Type(s): Functional

Summary: Mutation: K-RasG12D | Summary: The K-RasG12D mutation alters the growth response of myeloid progenitors to GM-CSF, exhibits resistance to GAP stimulation, and is associated with increased levels of Ras-GTP, pERK, and pAkt in Ba/F3 cells under serum deprivation, indicating multiple changes in molecular function related to signaling pathways and colony formation.

Evidence Type: Functional Mutation: A66dup | Summary: The A66dup mutation in K-Ras sensitizes myeloid progenitors to GM-CSF, alters molecular function by increasing levels of Ras-GTP in Ba/F3 cells under serum deprivation, reduces intrinsic GTP hydrolysis rates, and impairs PI3 kinase binding, demonstrating its impact on biochemical activity.

Evidence Type: Functional Mutation: Glutamine 61; Q61 | Summary: The Glutamine 61 (Q61) mutation may alter molecular function due to structural changes from switch 2 insertions, affecting protein-protein interactions and the GTP conformation of Ras.

Evidence Type: Functional Mutation: Y64G | Summary: The Y64G mutation in K-Ras, when combined with K-RasG12D, results in significantly reduced binding to FLAG-p110alpha, indicating an alteration in molecular function.

Gene→Variant (gene-first): KRAS(3845):K-RasG12D PIK3R1(5295):A66dup KRAS(3845):Glutamine 61 KRAS(3845):Q61 PIK3CA(5290):Y64G

Genes: KRAS(3845) PIK3R1(5295) PIK3CA(5290)

Variants: K-RasG12D A66dup Glutamine 61 Q61 Y64G

[Paragraph-level] PMCID: PMC4748120 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional, Diagnostic

Summary: Evidence Type: Oncogenic | Mutation: A66dup | Summary: The A66dup mutation in K-Ras is associated with tumor development and progression, as it transforms the growth of primary myeloid progenitors and Ba/F3 cells, indicating its oncogenic potential. Evidence Type: Functional | Mutation: A66dup | Summary: The A66dup mutation alters the molecular function of K-Ras by reducing intrinsic GTP hydrolysis rates and impairing PI3 kinase binding, demonstrating its impact on biochemical activity. Evidence Type: Diagnostic | Mutation: A66dup | Summary: The presence of the A66dup mutation in K-Ras has diagnostic implications, as it is associated with an atypical myeloproliferative neoplasm in the patient described.

Gene→Variant (gene-first): 5295:A66dup

Genes: 5295

Variants: A66dup

[Paper-level Aggregated] PMCID: PMC4695055

Evidence Type(s): Functional

Summary: 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.

Gene→Variant (gene-first): NTRK3(4916):p.982_1028del47

Genes: NTRK3(4916)

Variants: p.982_1028del47

[Paper-level Aggregated] PMCID: PMC4675689

Evidence Type(s): Functional

Summary: Mutation: D835 | Summary: The D835 mutation is critical for stabilizing the inactive conformation of FLT3, impacting molecular interactions necessary for type II inhibitor binding. It plays a role in stabilizing the DFG-out conformation of the kinase and affects the short alpha-helix coupled to the drug-binding site.

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 and preserving critical structural features necessary for the binding of type II inhibitors.

Evidence Type: Functional Mutation: D835Y | Summary: The D835Y mutation alters molecular interactions due to large and bulky hydrophobic amino acid residues, affecting 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.

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.

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.

Gene→Variant (gene-first): FLT3(2322):D835 FLT3(2322):D835E/N NA:D835Y NA:D835V FLT3(2322):D835H FLT3(2322):D835N/E

Genes: FLT3(2322) NA

Variants: D835 D835E/N D835Y D835V D835H D835N/E

[Paper-level Aggregated] PMCID: PMC4654747

Evidence Type(s): Functional

Summary: Mutation: K27M | Summary: The K27M mutation alters the trimethylation status of histone H3, impacting molecular function related to gene regulation in tumor cells. It is linked to alterations in molecular functions, specifically affecting adhesion properties and deregulating genes related to migration and invasion in tumors.

Evidence Type: Functional Mutation: K27I | Summary: The K27I mutation results in a loss of H3K27me3 immunoexpression, indicating an alteration in molecular function. The nucleotide changes 83A>T and 84G>T are part of the K27I mutation and contribute to the alteration in molecular function.

Gene→Variant (gene-first): H3-3B(3021):K27M H3-3B(3021):K27I

Genes: H3-3B(3021)

Variants: K27M K27I

[Paragraph-level] PMCID: PMC4654747 Section: RESULTS PassageIndex: 11

Evidence Type(s): Diagnostic, Prognostic, Functional

Summary: Evidence Type: Diagnostic | Mutation: K27M | Summary: The K27M mutation is associated with the proneural-glioblastoma multiforme subtype, indicating its role in classifying and defining this specific disease subtype. Evidence Type: Prognostic | Mutation: K27M | Summary: The presence of the K27M mutation correlates with disease outcome, as indicated by the clinico-radiological follow-up of DIPG patients showing a significant association with metastatic relapse. Evidence Type: Functional | Mutation: K27M | Summary: The K27M mutation is linked to alterations in molecular functions, specifically affecting adhesion properties and deregulating genes related to migration and invasion in tumors.

Gene→Variant (gene-first): 3021:K27M

Genes: 3021

Variants: K27M

[Paragraph-level] PMCID: PMC4654747 Section: RESULTS PassageIndex: 4

Evidence Type(s): Diagnostic, Oncogenic, Functional

Summary: Evidence Type: Diagnostic | Mutation: K27M | Summary: The H3-K27M mutation is used to classify and define a subtype of tumors, as it can be accurately detected by immunohistochemistry (IHC). Evidence Type: Oncogenic | Mutation: K27M | Summary: The H3-K27M mutation contributes to tumor development or progression, as indicated by its presence in tumor cells. Evidence Type: Functional | Mutation: K27I | Summary: The K27I mutation results in a loss of H3K27me3 immunoexpression, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: 83A>T | Summary: The nucleotide change 83A>T is part of the K27I mutation and contributes to the alteration in molecular function. Evidence Type: Functional | Mutation: 84G>T | Summary: The nucleotide change 84G>T is part of the K27I mutation and contributes to the alteration in molecular function.

Gene→Variant (gene-first): 7157:83A>T 4613:84G>T 3021:K27I 3021:K27M 126961:lysine-to-isoleucine

Genes: 7157 4613 3021 126961

Variants: 83A>T 84G>T K27I K27M lysine-to-isoleucine

[Paragraph-level] PMCID: PMC4654747 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: K27M | Summary: The H3-K27M mutation is associated with tumor development in DIPG, as indicated by its detection in biopsy samples and correlation with histological features. Evidence Type: Functional | Mutation: K27M | Summary: The K27M mutation alters the trimethylation status of histone H3, impacting molecular function related to gene regulation in tumor cells.

Gene→Variant (gene-first): 3021:K27M 3021:lysine 27

Genes: 3021

Variants: K27M lysine 27

[Paper-level Aggregated] PMCID: PMC4477877

Evidence Type(s): Functional

Summary: Mutation: L349P | Summary: The L349P mutation alters the localization and molecular function of the ETV6 protein, preventing it from localizing to the nucleus, impacting its regulatory function, and resulting in significantly decreased transcriptional repression compared to wild-type ETV6. It is also predicted to cause significant conformational changes and affects translation and subcellular localization.

Evidence Type: Functional Mutation: N385fs | Summary: The N385fs mutation results in an abnormally truncated ETV6 protein, impairing its ability to regulate the expression of target genes and exhibiting significantly decreased transcriptional repression compared to wild-type ETV6. It is also predicted to truncate the protein at a region involved in DNA interaction, suggesting a change in its biochemical function and affecting translation and subcellular localization.

Evidence Type: Functional Mutation: P214L | Summary: The P214L mutation demonstrates significantly decreased transcriptional repression compared to wild-type ETV6 and is detectable in both cytoplasmic and nuclear fractions, indicating a potential alteration in molecular function.

Evidence Type: Functional Mutation: R369Q | Summary: The R369Q mutation shows significantly reduced transcriptional repression compared to wild-type ETV6 and is present in both cytoplasmic and nuclear fractions, suggesting an alteration in molecular function.

Evidence Type: Functional Mutation: R399C | Summary: The R399C mutation exhibits significantly decreased transcriptional repression compared to wild-type ETV6 and is detectable in both cytoplasmic and nuclear fractions, indicating a potential change in molecular function.

Gene→Variant (gene-first): ETV6(2120):L349P ETV6(2120):N385fs ETV6(2120):P214L ETV6(2120):R369Q ETV6(2120):R399C

Genes: ETV6(2120)

Variants: L349P N385fs P214L R369Q R399C

[Paper-level Aggregated] PMCID: PMC4398541

Evidence Type(s): Functional

Summary: Mutation: L23F | Summary: The L23F mutation showed increased nuclear localization of PTEN and displayed compromised/partial PIP3 catalytic activity in yeast, indicating alterations in molecular function related to subcellular localization and enzymatic activity.

Evidence Type: Functional Mutation: M35R | Summary: The M35R mutation demonstrated increased nuclear localization of PTEN and resulted in a total loss of PTEN activity in a yeast model, indicating significant alterations in its molecular function.

Evidence Type: Functional Mutation: G36R | Summary: The G36R mutation resulted in increased nuclear localization of PTEN and caused a total loss of PTEN activity in a yeast model, indicating significant alterations in its molecular function.

Evidence Type: Functional Mutation: K13E | Summary: The K13E mutation fully abrogated the nuclear accumulation of PTEN 1-375 and resulted in a total loss of phosphatase activity in vivo, indicating significant alterations in its molecular function.

Evidence Type: Functional Mutation: A34D | Summary: The A34D mutation fully abrogated the nuclear accumulation of PTEN 1-375 and caused a total loss of PTEN activity in a yeast model, indicating significant alterations in its molecular function.

Evidence Type: Functional Mutation: L42P | Summary: The L42P mutation fully abrogated the nuclear accumulation of PTEN 1-375 and caused a total loss of PTEN activity in a yeast model, indicating significant alterations in its molecular function.

Evidence Type: Functional Mutation: R15I | Summary: The R15I mutation caused a partial inhibition of nuclear accumulation of PTEN and resulted in a total loss of PTEN activity in a yeast model, indicating significant alterations in its molecular function.

Evidence Type: Functional Mutation: R15S | Summary: The R15S mutation resulted in a partial inhibition of nuclear accumulation of PTEN and caused a total loss of PTEN activity in a yeast model, indicating significant alterations in its molecular function.

Evidence Type: Functional Mutation: D24Y | Summary: The D24Y mutation caused a partial inhibition of nuclear accumulation of PTEN and resulted in a total loss of PTEN activity in a yeast model, indicating significant alterations in its molecular function.

Evidence Type: Functional Mutation: I33S | Summary: The I33S mutation resulted in a partial inhibition of nuclear accumulation of PTEN and caused a total loss of PTEN activity in a yeast model, indicating significant alterations in its molecular function.

Evidence Type: Functional Mutation: S10N | Summary: The S10N mutation did not significantly alter the nuclear/cytoplasmic distribution of PTEN and partially reduced PTEN activity in a yeast model, suggesting no functional change.

Evidence Type: Functional Mutation: Y16C | Summary: The Y16C mutation did not significantly alter the nuclear/cytoplasmic distribution of PTEN and partially reduced PTEN activity in a yeast model, indicating a moderate alteration in molecular function.

Evidence Type: Functional Mutation: A34V | Summary: The A34V mutation did not significantly alter the nuclear/cytoplasmic distribution of PTEN and partially reduced PTEN activity in a yeast model, indicating a moderate alteration in molecular function.

Evidence Type: Functional Mutation: A39V | Summary: The A39V mutation alters the nuclear accumulation of PTEN and resulted in a complete loss-of-function of PTEN's PIP3 phosphatase activity, suggesting it alters molecular function.

Evidence Type: Functional Mutation: D19A | Summary: The D19A mutation affects the cytoplasmic localization of PTEN, suggesting an alteration in its molecular function.

Evidence Type: Functional Mutation: G20A | Summary: The G20A mutation influences the cytoplasmic localization of PTEN, indicating a change in its molecular function.

Evidence Type: Functional Mutation: F21A | Summary: The F21A mutation impacts the cytoplasmic localization of PTEN, suggesting an alteration in its molecular function.

Evidence Type: Functional Mutation: K13A | Summary: The K13A mutation inhibits nuclear entry of PTEN, indicating a change in its molecular function related to localization.

Evidence Type: Functional Mutation: R14A | Summary: The R14A mutation inhibits nuclear entry of PTEN, suggesting an alteration in its molecular function.

Evidence Type: Functional Mutation: R15A | Summary: The R15A mutation inhibits nuclear entry of PTEN and resulted in a complete loss-of-function of PTEN's PIP3 phosphatase activity, indicating an alteration in molecular function.

Evidence Type: Functional Mutation: E18A | Summary: The E18A mutation inhibits nuclear accumulation of PTEN, suggesting an alteration in its molecular function.

Evidence Type: Functional Mutation: D24A | Summary: The D24A mutation inhibits nuclear entry of PTEN and led to a complete loss-of-function of PTEN's PIP3 phosphatase activity, indicating a change in biochemical function.

Evidence Type: Functional Mutation: Y16A | Summary: The Y16A mutation inhibits nuclear entry of PTEN and displayed a complete loss-of-function in PTEN's PIP3 phosphatase activity, suggesting it alters molecular function.

Evidence Type: Functional Mutation: Y27A | Summary: The Y27A mutation inhibits nuclear entry of PTEN, indicating a change in its molecular function.

Evidence Type: Functional Mutation: I28A | Summary: The I28A mutation inhibits nuclear entry of PTEN, suggesting an alteration in its molecular function.

Evidence Type: Functional Mutation: N31A | Summary: The N31A mutation inhibits nuclear entry of PTEN and did not affect PIP3 catalytic activity in yeast, suggesting a change in molecular function.

Evidence Type: Functional Mutation: I32A | Summary: The I32A mutation inhibits nuclear entry of PTEN and resulted in a complete loss-of-function of PTEN's PIP3 phosphatase activity, reflecting an alteration in molecular function.

Evidence Type: Functional Mutation: I33A | Summary: The I33A mutation inhibits nuclear entry of PTEN and partially compromised PTEN activity, indicating an alteration in molecular function.

Evidence Type: Functional Mutation: P30A | Summary: The P30A mutation inhibits nuclear entry of PTEN, suggesting an alteration in its molecular function.

Evidence Type: Functional Mutation: N12A | Summary: The N12A mutation inhibits nuclear accumulation of PTEN, indicating a change in its molecular function.

Evidence Type: Functional Mutation: M35A | Summary: The M35A mutation inhibits nuclear accumulation of PTEN and caused a complete loss-of-function of PTEN's PIP3 phosphatase activity, indicating a change in biochemical function.

Evidence Type: Functional Mutation: L42A | Summary: The L42A mutation abrogated both nuclear accumulation and PIP3 phosphatase activity of PTEN, indicating a change in molecular function.

Evidence Type: Functional Mutation: K13R | Summary: The K13R mutation alters the nuclear localization of PTEN and enhances its ability to counteract PI3K activity in a yeast model.

Evidence Type: Functional Mutation: R14K | Summary: The R14K mutation affects the nuclear localization of PTEN and maintains its phosphatase activity in vivo.

Evidence Type: Functional Mutation: R15K | Summary: The R15K mutation increases the nuclear accumulation of PTEN but does not display phosphatase activity in vivo.

Gene→Variant (gene-first): PTEN(5728):L23F PTEN(5728):M35R PTEN(5728):G36R PTEN(5728):K13E PTEN(5728):A34D PTEN(5728):L42P PTEN(5728):R15I PTEN(5728):R15S PTEN(5728):D24Y PTEN(5728):I33S PTEN(5728):S10N PTEN(5728):Y16C PTEN(5728):A34V PTEN(5728):A39V ACTG1(71):D19A PTEN(5728):G20A PTEN(5728):F21A PTEN(5728):K13A AAA1(100329167):R14A PTEN(5728):R15A PTEN(5728):E18A PTEN(5728):D24A PTEN(5728):Y16A PTEN(5728):Y27A PTEN(5728):I28A PTEN(5728):N31A PTEN(5728):I32A PTEN(5728):I33A PTEN(5728):P30A PTEN(5728):N12A PTEN(5728):M35A PTEN(5728):L42A PTEN(5728):K13R AAA1(100329167):R14K PTEN(5728):R15K

Genes: PTEN(5728) ACTG1(71) AAA1(100329167)

Variants: L23F M35R G36R K13E A34D L42P R15I R15S D24Y I33S S10N Y16C A34V A39V D19A G20A F21A K13A R14A R15A E18A D24A Y16A Y27A I28A N31A I32A I33A P30A N12A M35A L42A K13R R14K R15K

[Paragraph-level] PMCID: PMC4398541 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L23F | Summary: The L23F mutation displays compromised/partial PIP3 catalytic activity in yeast, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: N31A | Summary: The N31A mutation did not affect PIP3 catalytic activity in yeast but impaired the nuclear accumulation of PTEN 1-375 in mammalian cells, suggesting a change in molecular function.

Gene→Variant (gene-first): 5728:L23F 5728:N31A

Genes: 5728

Variants: L23F N31A

[Paragraph-level] PMCID: PMC4398541 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K13R | Summary: The K13R mutation alters the nuclear localization of PTEN and enhances its ability to counteract PI3K activity in a yeast model. Evidence Type: Functional | Mutation: R14K | Summary: The R14K mutation affects the nuclear localization of PTEN and maintains its phosphatase activity in vivo. Evidence Type: Functional | Mutation: K13E | Summary: The K13E mutation results in a total loss of phosphatase activity in vivo. Evidence Type: Functional | Mutation: R15K | Summary: The R15K mutation increases the nuclear accumulation of PTEN but does not display phosphatase activity in vivo. Evidence Type: Functional | Mutation: K13A | Summary: The K13A mutation is part of a combined mutation that affects nuclear localization, indicating a role in PTEN's functional activity. Evidence Type: Functional | Mutation: R14A | Summary: The R14A mutation is part of a combined mutation that affects nuclear localization, indicating a role in PTEN's functional activity. Evidence Type: Functional | Mutation: R15A | Summary: The R15A mutation is part of a combined mutation that affects nuclear localization, indicating a role in PTEN's functional activity.

Gene→Variant (gene-first): 100329167:Arg14 5728:Arg15 5728:K13A 5728:K13E 5728:K13R 5728:Lys13 100329167:R14A 100329167:R14K 5728:R15A 5728:R15K

Genes: 100329167 5728

Variants: Arg14 Arg15 K13A K13E K13R Lys13 R14A R14K R15A R15K

[Paragraph-level] PMCID: PMC4398541 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: R15A | Summary: The R15A mutation resulted in a complete loss-of-function of PTEN's PIP3 phosphatase activity, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: Y16A | Summary: The Y16A mutation displayed a complete loss-of-function in PTEN's PIP3 phosphatase activity, suggesting it alters molecular function. Evidence Type: Functional | Mutation: D24A | Summary: The D24A mutation led to a complete loss-of-function of PTEN's PIP3 phosphatase activity, indicating a change in biochemical function. Evidence Type: Functional | Mutation: I32A | Summary: The I32A mutation resulted in a complete loss-of-function of PTEN's PIP3 phosphatase activity, reflecting an alteration in molecular function. Evidence Type: Functional | Mutation: M35A | Summary: The M35A mutation caused a complete loss-of-function of PTEN's PIP3 phosphatase activity, indicating a change in biochemical function. Evidence Type: Functional | Mutation: A39V | Summary: The A39V mutation resulted in a complete loss-of-function of PTEN's PIP3 phosphatase activity, suggesting it alters molecular function. Evidence Type: Functional | Mutation: I33A | Summary: The I33A mutation partially compromised PTEN activity, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: L42A | Summary: The L42A mutation abrogated both nuclear accumulation and PIP3 phosphatase activity of PTEN, indicating a change in molecular function.

Gene→Variant (gene-first): 5728:A39V 5728:D24A 5728:I32A 5728:I33A 5728:I5A 5728:K6A 5728:L42A 5728:M35A 5728:P38A 5728:Q17A 5728:R15A 5728:S10A 5728:Y16A

Genes: 5728

Variants: A39V D24A I32A I33A I5A K6A L42A M35A P38A Q17A R15A S10A Y16A

[Paragraph-level] PMCID: PMC4398541 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: A39V | Summary: The A39V mutation alters the nuclear accumulation of PTEN, indicating a change in its molecular function related to localization. Evidence Type: Functional | Mutation: D19A | Summary: The D19A mutation affects the cytoplasmic localization of PTEN, suggesting an alteration in its molecular function. Evidence Type: Functional | Mutation: G20A | Summary: The G20A mutation influences the cytoplasmic localization of PTEN, indicating a change in its molecular function. Evidence Type: Functional | Mutation: F21A | Summary: The F21A mutation impacts the cytoplasmic localization of PTEN, suggesting an alteration in its molecular function. Evidence Type: Functional | Mutation: K13A | Summary: The K13A mutation inhibits nuclear entry of PTEN, indicating a change in its molecular function related to localization. Evidence Type: Functional | Mutation: R14A | Summary: The R14A mutation inhibits nuclear entry of PTEN, suggesting an alteration in its molecular function. Evidence Type: Functional | Mutation: R15A | Summary: The R15A mutation inhibits nuclear entry of PTEN, indicating a change in its molecular function related to localization. Evidence Type: Functional | Mutation: E18A | Summary: The E18A mutation inhibits nuclear accumulation of PTEN, suggesting an alteration in its molecular function. Evidence Type: Functional | Mutation: D24A | Summary: The D24A mutation inhibits nuclear entry of PTEN, indicating a change in its molecular function. Evidence Type: Functional | Mutation: Y16A | Summary: The Y16A mutation inhibits nuclear entry of PTEN, suggesting an alteration in its molecular function. Evidence Type: Functional | Mutation: Y27A | Summary: The Y27A mutation inhibits nuclear entry of PTEN, indicating a change in its molecular function. Evidence Type: Functional | Mutation: I28A | Summary: The I28A mutation inhibits nuclear entry of PTEN, suggesting an alteration in its molecular function. Evidence Type: Functional | Mutation: N31A | Summary: The N31A mutation inhibits nuclear entry of PTEN, indicating a change in its molecular function. Evidence Type: Functional | Mutation: I32A | Summary: The I32A mutation inhibits nuclear entry of PTEN, suggesting an alteration in its molecular function. Evidence Type: Functional | Mutation: I33A | Summary: The I33A mutation inhibits nuclear entry of PTEN, indicating a change in its molecular function. Evidence Type: Functional | Mutation: P30A | Summary: The P30A mutation inhibits nuclear entry of PTEN, suggesting an alteration in its molecular function. Evidence Type: Functional | Mutation: N12A | Summary: The N12A mutation inhibits nuclear accumulation of PTEN, indicating a change in its molecular function. Evidence Type: Functional | Mutation: M35A | Summary: The M35A mutation inhibits nuclear accumulation of PTEN, suggesting an alteration in its molecular function.

Gene→Variant (gene-first): 5728:A39V 5728:Ala residues were mutated to Val 71:D19A 5728:D24A 5728:E18A 5728:F21A 5728:G20A 5728:I28A 5728:I32A 5728:I33A 5728:K13A 5728:L42A 5728:M35A 5728:N12A 5728:N31A 5728:P30A 100329167:R14A 5728:R15A 5728:Y16A 5728:Y27A

Genes: 5728 71 100329167

Variants: A39V Ala residues were mutated to Val D19A D24A E18A F21A G20A I28A I32A I33A K13A L42A M35A N12A N31A P30A R14A R15A Y16A Y27A

[Paragraph-level] PMCID: PMC4398541 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K13E | Summary: The K13E mutation totally abrogated PTEN activity in a yeast model, indicating a significant alteration in molecular function. Evidence Type: Functional | Mutation: R15I | Summary: The R15I mutation totally abrogated PTEN activity in a yeast model, indicating a significant alteration in molecular function. Evidence Type: Functional | Mutation: R15S | Summary: The R15S mutation totally abrogated PTEN activity in a yeast model, indicating a significant alteration in molecular function. Evidence Type: Functional | Mutation: D24Y | Summary: The D24Y mutation totally abrogated PTEN activity in a yeast model, indicating a significant alteration in molecular function. Evidence Type: Functional | Mutation: I33S | Summary: The I33S mutation totally abrogated PTEN activity in a yeast model, indicating a significant alteration in molecular function. Evidence Type: Functional | Mutation: A34D | Summary: The A34D mutation totally abrogated PTEN activity in a yeast model, indicating a significant alteration in molecular function. Evidence Type: Functional | Mutation: M35R | Summary: The M35R mutation totally abrogated PTEN activity in a yeast model, indicating a significant alteration in molecular function. Evidence Type: Functional | Mutation: G36R | Summary: The G36R mutation totally abrogated PTEN activity in a yeast model, indicating a significant alteration in molecular function. Evidence Type: Functional | Mutation: L42P | Summary: The L42P mutation totally abrogated PTEN activity in a yeast model, indicating a significant alteration in molecular function. Evidence Type: Functional | Mutation: S10N | Summary: The S10N mutation partially reduced PTEN activity in a yeast model, indicating a moderate alteration in molecular function. Evidence Type: Functional | Mutation: Y16C | Summary: The Y16C mutation partially reduced PTEN activity in a yeast model, indicating a moderate alteration in molecular function. Evidence Type: Functional | Mutation: L23F | Summary: The L23F mutation partially reduced PTEN activity in a yeast model, indicating a moderate alteration in molecular function. Evidence Type: Functional | Mutation: A34V | Summary: The A34V mutation partially reduced PTEN activity in a yeast model, indicating a moderate alteration in molecular function.

Gene→Variant (gene-first): 5728:A34D 5728:A34V 5728:D24Y 5728:G36R 5728:I33S 5728:K13E 5728:L23F 5728:L42P 5728:M35R 5728:R15I 5728:R15S 5728:S10N 5728:Y16C

Genes: 5728

Variants: A34D A34V D24Y G36R I33S K13E L23F L42P M35R R15I R15S S10N Y16C

[Paragraph-level] PMCID: PMC4398541 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: L23F | Summary: The L23F mutation showed increased nuclear localization of PTEN, indicating an alteration in molecular function related to subcellular localization. Evidence Type: Functional | Mutation: M35R | Summary: The M35R mutation demonstrated increased nuclear localization of PTEN, suggesting a change in its molecular function. Evidence Type: Functional | Mutation: G36R | Summary: The G36R mutation resulted in increased nuclear localization of PTEN, reflecting an alteration in its molecular function. Evidence Type: Functional | Mutation: K13E | Summary: The K13E mutation fully abrogated the nuclear accumulation of PTEN 1-375, indicating a significant change in its molecular function. Evidence Type: Functional | Mutation: A34D | Summary: The A34D mutation fully abrogated the nuclear accumulation of PTEN 1-375, suggesting an alteration in its molecular function. Evidence Type: Functional | Mutation: L42P | Summary: The L42P mutation fully abrogated the nuclear accumulation of PTEN 1-375, indicating a change in its molecular function. Evidence Type: Functional | Mutation: R15I | Summary: The R15I mutation caused a partial inhibition of nuclear accumulation of PTEN, reflecting an alteration in its molecular function. Evidence Type: Functional | Mutation: R15S | Summary: The R15S mutation resulted in a partial inhibition of nuclear accumulation of PTEN, indicating a change in its molecular function. Evidence Type: Functional | Mutation: D24Y | Summary: The D24Y mutation caused a partial inhibition of nuclear accumulation of PTEN, suggesting an alteration in its molecular function. Evidence Type: Functional | Mutation: I33S | Summary: The I33S mutation resulted in a partial inhibition of nuclear accumulation of PTEN, indicating a change in its molecular function. Evidence Type: Functional | Mutation: S10N | Summary: The S10N mutation did not significantly alter the nuclear/cytoplasmic distribution of PTEN, suggesting no functional change. Evidence Type: Functional | Mutation: Y16C | Summary: The Y16C mutation did not significantly alter the nuclear/cytoplasmic distribution of PTEN, indicating no functional change. Evidence Type: Functional | Mutation: A34V | Summary: The A34V mutation did not significantly alter the nuclear/cytoplasmic distribution of PTEN, suggesting no functional change.

Gene→Variant (gene-first): 5728:A34D 5728:A34V 5728:D24Y 5728:G36R 5728:I33S 5728:K13E 5728:L23F 5728:L42P 5728:M35R 5728:R15I 5728:R15S 5728:S10N 5728:Y16C

Genes: 5728

Variants: A34D A34V D24Y G36R I33S K13E L23F L42P M35R R15I R15S S10N Y16C

[Paper-level Aggregated] PMCID: PMC4234187

Evidence Type(s): Functional

Summary: Mutation: C118S | Summary: The C118S mutation alters the molecular function of Ras by blocking activation, affecting the ability of eNOS to stimulate the MAPK pathway, and influencing signaling pathways related to oncogenic activity. It also alters tumor size and incidence of adenomas, as evidenced by reduced P-Akt levels and changes in P-Erk1/2 levels upon EGF treatment. Additionally, the presence of the KrasC118S allele suggests a change in molecular or biochemical function, although specific functional impacts are not detailed.

Evidence Type: Functional Mutation: S1177D | Summary: The S1177D mutation in eNOS alters the levels of phosphorylated Erk1/2, demonstrating a change in biochemical function.

Evidence Type: Functional Mutation: G13D | Summary: The G13D mutation, when combined with C118S, affects the molecular function of Kras, influencing signaling pathways related to oncogenic activity.

Gene→Variant (gene-first): NOS2(4843):C118S NOS3(4846):S1177D KRAS(3845):G13D

Genes: NOS2(4843) NOS3(4846) KRAS(3845)

Variants: C118S S1177D G13D

[Paragraph-level] PMCID: PMC4234187 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: C118S | Summary: The C118S mutation in the Kras gene is investigated for its role in tumorigenesis, showing that it impedes urethane-induced lung tumor development, indicating its contribution to cancer progression. Evidence Type: Functional | Mutation: C118S | Summary: The C118S mutation alters the molecular function of the Kras protein, as it affects the activation and subsequent tumorigenic potential in response to carcinogen exposure.

Gene→Variant (gene-first): 4843:C118 4843:C118S 4843:cysteine 118

Genes: 4843

Variants: C118 C118S cysteine 118

[Paper-level Aggregated] PMCID: PMC4159563

Evidence Type(s): Functional

Summary: Mutation: p.Glu545Gly | Summary: The p.Glu545Gly alteration in PIK3CA is a mutation that may alter the molecular function of the protein, contributing to tumorigenesis.

Evidence Type: Functional Mutation: p.Gly328Val | Summary: The p.Gly328Val substitution in ACVR1 is a mutation that may affect the molecular function of the protein, potentially playing a role in tumor development.

Gene→Variant (gene-first): PIK3CA(5290):p.Glu545Gly ACVR1(90):p.Gly328Val

Genes: PIK3CA(5290) ACVR1(90)

Variants: p.Glu545Gly p.Gly328Val

[Paragraph-level] PMCID: PMC4159563 Section: RESULTS PassageIndex: 7

Evidence Type(s): Prognostic, Oncogenic, Functional

Summary: Evidence Type: Prognostic | Mutation: K27M | Summary: The K27M mutation is associated with worse overall survival in patients with leptomeningeal spread, averaging 0.63 years compared to 1.84 years for wild-type cases. Evidence Type: Oncogenic | Mutation: K27M | Summary: The K27M mutation contributes to tumor development, as indicated by its presence in cases of GBM and its association with leptomeningeal dissemination. Evidence Type: Functional | Mutation: p.Glu545Gly | Summary: The p.Glu545Gly alteration in PIK3CA is a mutation that may alter the molecular function of the protein, contributing to tumorigenesis. Evidence Type: Functional | Mutation: p.Gly328Val | Summary: The p.Gly328Val substitution in ACVR1 is a mutation that may affect the molecular function of the protein, potentially playing a role in tumor development.

Gene→Variant (gene-first): 90:K27M 5290:p.Glu545Gly 90:p.Gly328Val

Genes: 90 5290

Variants: K27M p.Glu545Gly p.Gly328Val