[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variant p.L1407P disrupts the interaction of BRCA1 with PALB2 and predicts that it disables the alpha-helical structure of the coiled-coil domain, indicating an alteration in molecular function. Oncogenic: The use of CRISPR/Cas9 to model the BRCA1 variant in mice suggests that the variant contributes to tumor development or progression, as it is being studied in the context of a gene essential for embryonic development and cancer biology.

Gene→Variant (gene-first): 672:4220T>C 7158:p.L1363P 672:p.L1407P

Genes: 672 7158

Variants: 4220T>C p.L1363P p.L1407P

[Paragraph-level] PMCID: PMC2789045 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the FGFR3 mutations (S249C, Y375C, and K652E) alter molecular signaling pathways, specifically the phosphorylation of various proteins, indicating a change in biochemical function. Oncogenic: The passage describes how the mutant FGFR3 variants induce morphological transformation, cell proliferation, and anchorage-independent growth, which are indicative of their role in tumor development and progression.

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

Genes: 2261

Variants: K652E S249C Y375C

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the S249C and K652E mutations affect cell viability and signaling pathways, indicating that these variants alter molecular or biochemical functions related to cell growth and density. Oncogenic: The evidence suggests that the S249C and K652E mutations contribute to tumor development or progression by affecting cell cycle phases and viability, which are indicative of cancer-driving behavior.

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

Genes: 2261

Variants: K652E S249C Y762F

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the S249C+Y762F FGFR3 mutant protein's ability to induce morphological transformation and increased proliferation in NIH-3T3 cells, indicating its role in tumor development or progression. Functional: The passage describes how the S249C+Y762F mutation affects the phosphorylation of PLCgamma1 and alters the activation of downstream signaling pathways, demonstrating a change in molecular function.

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

Genes: 2261

Variants: K652E S249C Y762F

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the K652E, S249C, and Y375C mutations alter the signaling response to FGF1 treatment, indicating that these variants affect molecular function related to phosphorylation and activation of signaling pathways. Oncogenic: The context of the mutations being discussed in relation to their effects on signaling pathways suggests that they may contribute to tumor development or progression, particularly given the focus on their responses in cancer-related cellular contexts.

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

Genes: 2261

Variants: K652E S249C Y375C

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

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the response of cells expressing mutant FGFR3 variants (S249C, Y375C, K652E) to FGF1 stimulation, indicating a correlation with receptor activation and signaling, which relates to treatment response. Functional: The passage describes how the variants S249C, Y375C, and K652E affect the phosphorylation of FGFR3, indicating that these mutations alter the molecular function of the receptor in response to ligand stimulation.

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

Genes: 2261

Variants: K652E S249C Y375C

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the increased phosphorylation of PLCgamma1 specifically in cells expressing the S249C and Y375C FGFR3 variants, indicating that these variants alter molecular function. Oncogenic: The mention of increased phosphorylation of signaling proteins in cells expressing the FGFR3 mutants suggests that these variants contribute to tumor development or progression.

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

Genes: 2261

Variants: K652E S249C Y375C

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the K652E, S249C, and Y375C variants of FGFR3 alter phosphorylation levels and dimerization behavior, indicating changes in molecular function. Oncogenic: The variants are described in the context of their constitutive activation and behavior in urothelial cells, suggesting their role in tumor development or progression.

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

Genes: 2261

Variants: K652E S249C Y375C

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the expression of proteins involved in cell survival and suggests that the K652E variant may alter the viability of cells, indicating a change in molecular function. Oncogenic: The context implies that the K652E variant contributes to tumor behavior by affecting cell viability, which is a characteristic of oncogenic variants.

Gene→Variant (gene-first): 2261:K652E

Genes: 2261

Variants: K652E

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variants S249C, Y375C, and K652E FGFR3 alter the expression and phosphorylation of cell cycle-related proteins, indicating a change in molecular function.

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

Genes: 2261

Variants: K652E S249C Y375C

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the viability of cells expressing specific variants (S249C and Y375C) compared to controls, indicating that these variants alter the molecular or biochemical function of FGFR3, affecting cell viability. Oncogenic: The evidence suggests that the variants S249C and Y375C contribute to tumor development or progression by enhancing cell viability, which is a characteristic of oncogenic behavior.

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

Genes: 2261

Variants: K652E S249C Y375C

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

Evidence Type(s): Functional

Justification: Functional: The mention of K652E and Y375C variants also suggests alterations in cell cycle profiles, indicating a change in molecular function related to cell cycle dynamics.

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

Genes: 2261

Variants: K652E S249C Y375C

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

Evidence Type(s): Diagnostic, Functional

Justification: Diagnostic: The passage discusses the relative frequencies of the mutations K652E, S249C, and Y375C in bladder tumors, indicating an association with the disease. Functional: The passage mentions the phenotypic effects of the variants, suggesting that they alter the behavior of cells expressing these mutations compared to controls.

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

Genes: 2261

Variants: K652E S249C Y375C

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the expression of mutant FGFR3 variants S249C and Y375C alters the saturation density and morphology of normal urothelial cells, indicating a change in molecular or biochemical function. Oncogenic: The expression of the mutant FGFR3 variants is associated with changes in cell behavior, such as increased saturation density and altered morphology, which suggests a contribution to tumor development or progression.

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

Genes: 2261

Variants: K652E S249C Y375C

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the ability of the FGFR3 mutations (S249C, Y375C, and K652E) to transform NIH-3T3 cells, indicating that these somatic variants contribute to tumor development or progression. Functional: The passage describes how the FGFR3 mutations alter molecular function, specifically through increased phosphorylation of various proteins and changes in cell morphology and proliferation, demonstrating their biochemical activity.

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

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC7099049 Section: ABSTRACT PassageIndex: 3

Evidence Type(s): Prognostic, Functional

Justification: Prognostic: The passage discusses the association of SNPs with HNSCC survival, indicating that these variants correlate with disease outcome, specifically overall survival, independent of therapy. Functional: The passage mentions that the genotype of rs16879870 and rs854936 is significantly associated with the expression of specific genes in cancer tissues, suggesting that these variants alter molecular function.

Gene→Variant (gene-first): NA:rs16879870 388325:rs2641256 341019:rs2761591 NA:rs854936

Genes: NA 388325 341019

Variants: rs16879870 rs2641256 rs2761591 rs854936

[Paragraph-level] PMCID: PMC7612475 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Functional

Justification: Predictive: The K700E mutation in SF3B1 increases cellular sensitivity to ionising radiation and various chemotherapeutic agents, including PARP inhibitors, indicating a correlation with treatment response. Functional: The K700E mutation alters HR efficiency and induces unscheduled R-loop formation, replication fork stalling, and defective replication fork restart, demonstrating an impact on molecular function.

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

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC3542862 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses somatic mutations in PIK3CA (including R115P, E542K, H1047L, and H1047R) that contribute to the pathophysiology of macrodactyly, indicating their role in tumor development or progression through activation of the PI3K/AKT signaling pathway. Functional: The passage mentions that the identified mutations lead to AKT activation, which indicates that these variants alter molecular or biochemical function related to cell signaling pathways.

Gene→Variant (gene-first): 5290:E542K 5290:H1047L 5290:H1047R 5163:R115P

Genes: 5290 5163

Variants: E542K H1047L H1047R R115P

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how mutations at amino acids p.Glu542 and p.His1047 increase intracellular AKT phosphorylation, indicating an alteration in molecular function related to AKT activation. Oncogenic: The mention of increased AKT phosphorylation due to the H1047R mutation suggests that this somatic variant contributes to tumor development or progression by promoting cellular processes such as survival and proliferation.

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

Genes: 5290

Variants: H1047R p.Glu542 p.His1047

[Paragraph-level] PMCID: PMC3542862 Section: RESULTS PassageIndex: 6

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses somatic mutations in the PIK3CA gene, specifically mentioning that the E542K, H1047R, and H1047L mutations are known gain-of-function mutations frequently mutated in cancer, indicating their contribution to tumor development or progression. Functional: The passage notes that the mutations E542K and H1047 (both H1047R and H1047L) are located in the helical and kinase domains of the PI3K protein, which are known hotspots for somatic gain-of-function mutations, suggesting that these variants alter the molecular function of the protein.

Gene→Variant (gene-first): 5290:E542K 5290:H1047L 5290:H1047R 5163:R115P 5290:p.Glu542 5290:p.His1047

Genes: 5290 5163

Variants: E542K H1047L H1047R R115P p.Glu542 p.His1047

[Paragraph-level] PMCID: PMC9837058 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how mutations in PIK3CA, including G1049R, H1047R, and M1043I/L, contribute to the activation of the PI3K pathway, indicating their role in tumor development or progression. Functional: The passage describes how specific mutations alter the conformation and binding properties of the p110alpha subunit, indicating that these variants affect molecular function related to PI3K activation.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043I/L

Genes: 5290

Variants: G1049R H1047R M1043I/L

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 19

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the H1047R variant alters the binding interactions and structural dynamics of the protein in response to pY binding, indicating a change in molecular function.

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

Genes: 5290

Variants: H1047R

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 18

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the H1047R and G1049R variants alter the molecular interactions and conformations within the kinase domain, indicating a change in biochemical function related to the protein's activity. Oncogenic: The evidence suggests that the H1047R and G1049R variants contribute to activation through disruption of the inhibitory conformation, which is indicative of their role in tumor development or progression.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 17

Evidence Type(s): Functional

Justification: Functional: The passage discusses changes observed for the H1047R variant in the context of HDX-MS experiments, indicating that it alters molecular or biochemical function, specifically in terms of perturbations in conformation.

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

Genes: 5290

Variants: H1047R

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how C-terminal mutations, including M1043L, H1047R, G1049R, and N1068fs, affect the inhibitory interaction with the C-terminus, indicating an alteration in molecular function. Oncogenic: The mention of "oncogenic mutation" in relation to M1043L, H1047R, and G1049R suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants H1047R, G1049R, M1043L, and N1068fs alter membrane binding and ATPase activity, indicating changes in molecular function. Oncogenic: The variants are described in the context of their effects on membrane binding and ATPase activity, which suggests a role in tumor development or progression.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the intrinsic ATPase activity of the p110alpha mutants, indicating that the variants G1049R, H1047R, and M1043L alter molecular function by exhibiting significantly increased ATPase activity compared to wild type. Oncogenic: The context of the passage implies that the variants are somatic mutations in a cancer-related gene, contributing to tumor development or progression through their altered biochemical activity.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 12

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses frequent oncogenic mutants and their role in tumor samples, indicating that these variants contribute to tumor development or progression. Functional: The analysis of the mutants and their binding to full-length p85alpha suggests that these variants alter molecular or biochemical function, specifically in the context of their interaction with regulatory complexes.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:H1047R/L 5290:M1043L 5290:M1043L/I 5290:N1044K 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R H1047R/L M1043L M1043L/I N1044K N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the H1047R mutation in the context of its role in activating the kinase domain and increasing membrane binding, indicating its contribution to tumor development or progression. Functional: The passage describes how the H1047R mutation alters the molecular interactions and structural organization of the kinase domain, affecting its binding properties and functionality.

Gene→Variant (gene-first): 5290:H1047R 5290:His1047 5290:Met1043

Genes: 5290

Variants: H1047R His1047 Met1043

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the E726K variant in the context of oncogenic mutations and its association with conformational changes that contribute to tumor development, indicating its role in cancer progression. Functional: The passage describes how the E726K variant leads to conformational changes affecting the interaction between the ABD and p85 with the catalytic core, suggesting an alteration in molecular function.

Gene→Variant (gene-first): 5290:E726K

Genes: 5290

Variants: E726K

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the N345K variant affects the molecular interactions and binding of the p110alpha/p85alpha complex to membranes, indicating an alteration in biochemical function.

Gene→Variant (gene-first): 5290:N345K

Genes: 5290

Variants: N345K

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses oncogenic mutants (N345K, G106V, and G118D) and their expected role in promoting ABD/iSH2 disengagement, indicating their contribution to tumor development or progression. Functional: The data suggests that the variants alter the dynamics of the ABD-p85 complex and its interaction with the p110alpha catalytic core, indicating a change in molecular function related to binding and mobility.

Gene→Variant (gene-first): 5290:G106V 5290:G118D 5290:N345K

Genes: 5290

Variants: G106V G118D N345K

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 2

Evidence Type(s): Functional

Justification: Functional: The passage discusses the D915N mutation in the context of its effect on protein conformation and membrane binding, indicating that it alters molecular function as assessed by HDX-MS experiments.

Gene→Variant (gene-first): 5290:D915N

Genes: 5290

Variants: D915N

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the effects of the ERBB2 E401G and S310F variants on the proliferative and invasive capacities of cancer cells, indicating that these variants alter molecular or biochemical functions related to cell behavior. Oncogenic: The evaluation of the proliferative and invasive capacities of cells expressing the ERBB2 variants suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 2176:E401G 2064:S310F

Genes: 2176 2064

Variants: E401G S310F

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants E401G and S310F alter the phosphorylation of downstream signaling pathway proteins, indicating a change in molecular function related to the MAPK pathway. Oncogenic: The evidence suggests that the variants contribute to tumor development or progression by activating signaling pathways associated with cancer, specifically through the ERBB2 dimerization and its effects on downstream signaling.

Gene→Variant (gene-first): 2176:E401G 2064:S310F

Genes: 2176 2064

Variants: E401G S310F

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the E401G and S310F mutations affect the dimer interface stability of the EGFR-HER2 complex, indicating that these variants alter molecular interactions and stability.

Gene→Variant (gene-first): 2176:E401G 2064:S310F

Genes: 2176 2064

Variants: E401G S310F

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional

Justification: Functional: The passage indicates that the variant p.(E401G) alters the stability of the ligand-free EGFR HER2 heterodimer, which suggests a change in molecular function.

Gene→Variant (gene-first): 2176:p.(E401G)

Genes: 2176

Variants: p.(E401G)

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants E401G and S310F lead to increased phosphorylation levels of HER2 and EGFR, indicating that these variants alter molecular function related to protein activity. Oncogenic: The context of the passage suggests that the variants E401G and S310F contribute to tumor development or progression by enhancing the phosphorylation of key HER family proteins involved in oncogenesis.

Gene→Variant (gene-first): 2176:E401G 2064:S310F

Genes: 2176 2064

Variants: E401G S310F

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional

Justification: Functional: The passage discusses the identification of potential dimerization partners of the HER2 E401G protein, indicating that the variant alters molecular interactions.

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variants S310F and E401G alter the C-terminal phosphorylation of HER2, indicating a change in molecular function.

Gene→Variant (gene-first): 2176:E401G 2064:S310F

Genes: 2176 2064

Variants: E401G S310F

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional

Justification: Functional: The passage discusses the ability of the variants E321G, E401G, and S310F to form disulfide-linked dimers, indicating that these variants alter molecular function related to protein interactions.

Gene→Variant (gene-first): 7157:E321G 2176:E401G 2064:S310F

Genes: 7157 2176 2064

Variants: E321G E401G S310F

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional

Justification: Functional: The passage mentions the evaluation of mechanisms for multiple ERBB2 variants, including E321G, E401G, S310F, and D845A, which suggests that these variants are being assessed for their biochemical functions.

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

Genes: 2064 7157 2176

Variants: D845A E321G E401G S310F

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Justification: Functional: The passage indicates that ERBB2 E401G has functional properties similar to S310F, suggesting that these variants alter molecular or biochemical function.

Gene→Variant (gene-first): 2176:E401G 2064:S310F

Genes: 2176 2064

Variants: E401G S310F

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage describes the ERBB2 E401G variant as a somatic mutation that is associated with ERBB2 gene amplification, indicating its contribution to tumor development or progression. Functional: The passage mentions that multiple computational tools supported a deleterious effect of the ERBB2 E401G variant on the encoded gene product, suggesting that it alters molecular or biochemical function.

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

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

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses how gilteritinib inhibits FLT3-D835Y and FLT3-ITD-D835Y, indicating a correlation between the variant and response to the therapy, which is a predictive context. Functional: The passage describes how gilteritinib interacts with FLT3 at the F691 position and discusses the structural implications of the D835Y mutation, indicating an alteration in molecular function related to the binding of the inhibitor.

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

Genes: 2322

Variants: D835 D835Y F691

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage indicates that the PIK3CA H1047R mutation contributes to tumor development and progression, as it is associated with high-grade astrocytoma (WHO IV) and is linked to localized survival and growth advantages in tumor areas where it is acquired. Functional: The H1047R mutation affects the catalytic domain of PIK3CA, suggesting that it alters the molecular function of the protein, which is further supported by the mention of its role in PI3K activation and associated pathways.

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

Genes: 5290

Variants: H1047R

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

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The passage discusses the HER3 V855A somatic mutation's role in the development and progression of non-small cell lung cancer (NSCLC), indicating its contribution to tumor behavior. Predictive: The text mentions that HER-targeted inhibitors potently suppress mutant HER3 activity, suggesting a correlation between the V855A variant and response to targeted therapies. Functional: The passage states that in silico computational 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

Justification: Functional: The passage indicates that the V855A mutation alters the activity of HER3, which relates to its molecular function. Oncogenic: The mention of the V855A mutation correlating with a malignant phenotype suggests that it contributes 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

Justification: Functional: The passage discusses how the V855A mutation alters the conformation of the wild-type HER3 protein, indicating a change in molecular function related to the kinase domain.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses the impact of the V855A variant on HER3 protein structure, indicating that it alters molecular or biochemical function.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

[Paragraph-level] PMCID: PMC4823091 Section: RESULTS PassageIndex: 21

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the growth inhibitory effects of various inhibitors on cells expressing the HER3-V855A variant, indicating a correlation between the variant and response to specific therapies, such as afatinib and erlotinib. Functional: The variant HER3-V855A is examined in the context of its effect on cell growth and response to inhibitors, suggesting that it alters the molecular function of the HER3 receptor in relation to drug sensitivity.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the V855A mutation alters the physical interaction between HER3 and HER2, indicating a change in molecular function through enhanced interaction, which is supported by co-immunoprecipitation experiments.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the HER3-V855A variant enhances trans-phosphorylation of HER2, indicating an alteration in molecular function related to 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

Justification: Functional: The passage discusses how the V855A variant alters the phosphorylation levels of HER3 and AKT, indicating a change in molecular function related to signaling pathways. Oncogenic: The text implies that the V855A variant contributes to transforming activity, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the functional relevance of the HER3-V855A variant, indicating that it alters the growth response of Ba/F3 cells when co-expressed with EGFR, demonstrating a change in molecular function related to TGFalpha treatment. Oncogenic: The passage implies that the HER3-V855A mutation has pathogenic effects, suggesting a role in tumor development or progression, particularly in the context of its interaction with EGFR and response to growth factors.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the ability of the HER3-V855A variant to alter colony size in response to treatment, indicating a change in molecular or biochemical function. Oncogenic: The variant HER3-V855A is implicated in colony formation, which suggests its role in tumor development or progression.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the transforming potential of the HER3-V855A variant in the context of IL-3-independent growth, indicating that this somatic variant contributes to tumor development or progression as evidenced by the growth response in Ba/F3 cells. Functional: The variant HER3-V855A alters the growth response of Ba/F3 cells when stimulated with NRG1beta, demonstrating a change in molecular function related to HER3/HER2 biological activity.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the HER3-V855A variant in the context of oncogenic transformation and tumorigenesis, indicating that it may contribute to tumor development when co-expressed with HER2. Functional: The study investigates the functional impact of the HER3-V855A variant in a cellular model, focusing on its properties and effects on cell behavior in a controlled environment.

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the V855A mutation may have a functional effect by altering protein kinase activity, as indicated by its position in a conserved sequence motif and its analysis through structural studies. Oncogenic: The mention of the BRAF-L597V mutation being classified as an intermediate kinase active variant that increases ERK activation suggests that the V855A mutation may contribute to tumor development or progression through its functional implications.

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: PMC7064492 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses MAP2K1 mutations, including p.K57N, in the context of their presence in endothelial cells and their role in local tissue overgrowth associated with arteriovenous malformation (AVM), indicating a contribution to tumor development or progression. Functional: The study investigates the effects of the MAP2K1 mutation on local tissue overgrowth, suggesting that the variant alters molecular or biochemical function in the context of AVM pathology.

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

Genes: 5604

Variants: p.K57N

[Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 43

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how specific mutations (e.g., G142V, M523V, G524D, M537V) alter transactivational activity and regulatory element binding, indicating changes in molecular function. Oncogenic: The analysis of mutations in the context of prostate cancer (PCa) suggests that these variants contribute to tumor development or progression, particularly through their effects on transactivational activity related to cancer-related genes.

Gene→Variant (gene-first): 2232:G142V 367:G524D 367:M523V 367:M537V 1387:M749I 10514:Q798E 10499:R629Q 10499:T575A

Genes: 2232 367 1387 10514 10499

Variants: G142V G524D M523V M537V M749I Q798E R629Q T575A

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the M886I variant may drive cancer progression through altered binding and other mechanisms, indicating its role in tumor development. Functional: The passage mentions that the M886I variant may alter binding to co-repressors or co-regulators, which suggests a change in molecular function.

Gene→Variant (gene-first): 9611:M886I

Genes: 9611

Variants: M886I

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants M749I, Q798E, and H874Y alter the molecular function of the androgen receptor, specifically in terms of their constitutive activity and loss of function in response to DHT. Oncogenic: The passage indicates that the mutations M749I, Q798E, and H874Y may contribute to prostate cancer development and progression, particularly through their effects on androgen receptor signaling and activity.

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

Genes: 367 1387 10514

Variants: H874Y M749I Q798E

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the mutations T575A, R629Q, and I672T alter the molecular function of the androgen receptor (AR), affecting its binding and transactivation capabilities, indicating a change in biochemical activity. Oncogenic: The passage mentions that the mutation K630 to glutamine increases transactivational activity and promotes prostate cancer cell survival and growth, suggesting that this variant contributes to tumor development or progression.

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

Genes: 2908 10499

Variants: I672 I672T R629 R629Q T575A

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants L57Q, G142V, P390L, and P533S alter the function of the androgen receptor, indicating changes in activity in response to DHT, which aligns with evidence of altered molecular or biochemical function. Oncogenic: The variants are described in the context of their roles in tumor development or progression, particularly with references to gain or loss of function in the androgen receptor, which is relevant to cancer biology.

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

Genes: 2232 367

Variants: G142V L57Q P390L P533S

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the AR mutations P390L, T575A, and R629Q affect the molecular function of the androgen receptor, specifically its affinity for regulatory elements, indicating a change in biochemical activity.

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

Genes: 367 10499

Variants: P390L R629Q T575A

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the mutations D879G, H874Y, Q919R, and T877A alter the molecular or biochemical function of the protein, specifically in terms of gain or loss of function and ligand binding activity. Oncogenic: The mention of the mutated AR being expressed in a commonly used prostate cancer cell line (LNCaP) suggests that these mutations may contribute to tumor development or progression.

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

Genes: 10499 367

Variants: D879G H874Y Q919R T877A

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

Evidence Type(s): Predisposing, Functional

Justification: Predisposing: The variant K720E is implicated in a 6-fold increased risk of prostate cancer, indicating its role in inherited risk for developing the disease. Functional: The passage discusses how mutations K720E and R726L impair binding of co-regulatory proteins and disrupt interactions, indicating that these variants alter molecular function. Additionally, N756's mutation to aspartate resulted in complete loss of function, further supporting its functional impact.

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

Genes: 367 9611

Variants: A765T K720E N756 Q902 Q902R R726L Y763C lysine 720

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how specific mutations, including V757A and Q798E, show impaired binding to co-regulatory proteins and altered transactivational activity, indicating changes in molecular function. Oncogenic: The mention of loss of function mutations clustered in the ligand binding domain (LBD) and their association with reduced transactivational activity suggests a role in tumor development or progression, particularly in the context of antiandrogen treatment.

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

Genes: 367 9611 1387 10514

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

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the M886I mutation alters the interaction of the androgen receptor (AR) with co-activators and co-repressors, affecting transactivation ability, which indicates a change in molecular function. Oncogenic: The passage implies that the M886I mutation could significantly alter activity in prostate cancer, suggesting a role in tumor development or progression.

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

Genes: 367 9611

Variants: K910R M886 M886I

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variants A586V, A587S, T575A, R629Q, and I672T alter molecular function, specifically their effects on transactivational activity and ligand binding in response to different concentrations of DHT.

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

Genes: 597 367 2908 10499

Variants: A586V A587S I672T R629Q T575A

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the mutations (including P533S, G142V, M523V, G524D, and M537V) alter the transactivation activity of the androgen receptor, indicating that these variants affect molecular function related to protein activity in response to DHT. Oncogenic: The passage implies that the mutations contribute to prostate cancer by leading to constitutive transactivation activity, which is a characteristic of oncogenic variants that drive tumor development.

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

Genes: 2232 367

Variants: G142V G524D M523V M537V P533S

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants P269S, P390L, P514S, and S515G alter transactivational activity in response to DHT, indicating a change in molecular function. Oncogenic: The mention of the variants impacting AR signaling suggests a role in tumor development or progression, as alterations in androgen receptor signaling are often associated with cancer.

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

Genes: 367 10514

Variants: P269S P390L P514S S515G

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the S296R mutation alters interaction with the co-repressor N-CoR, causing reduced transactivational activity, and how the P340L mutation affects binding with TFIIF, indicating changes in molecular function. Oncogenic: The passage describes how the P340L mutation can drive prostate cancer progression through reduced growth suppression, indicating its role in tumor development.

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

Genes: 207 367 2232 9611

Variants: D221H D528G E198G P269S P340L P504L S296R S334P

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the mutations L57Q, E198G, D221H, A234T, S296R, S334P, P340L, P504L, and D528G result in loss of function, indicating that these variants alter molecular or biochemical function. Oncogenic: The mention of mutations leading to loss of function and their association with transactivational ability suggests a role in tumor development or progression, particularly in the context of the mutations being present in AIS (androgens insensitivity syndrome).

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

Genes: 1387 207 367 2232 9611

Variants: A234T D221H D528G E198G L57Q P340L P504L S296R S334P

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage indicates that the mutation M537R shows a 23% gain of function at a specific concentration of DHT, suggesting an alteration in molecular or biochemical function. Oncogenic: The mention of gain of function in a low androgen environment implies that the variant may contribute to tumor development or progression, characteristic of oncogenic behavior.

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

Genes: 367

Variants: G166S M537R

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses the conservation and divergence of specific amino acids (T575, R629, I672) in relation to the function of the ligand-binding domain (LBD) of the androgen receptor, indicating that these variants may alter molecular function related to androgen binding.

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

Genes: 2908 10499

Variants: I672 R629 T575

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

Evidence Type(s): Diagnostic, Functional

Justification: Diagnostic: The passage discusses the conservation of mutated residues in the AR gene and their association with prostate cancer (PCa), indicating that these variants are used to classify or define a disease subtype. Functional: The passage mentions examining amino acids implicated in prostate cancer and suggests a possible role in the mechanics of AR function, indicating that these variants may alter molecular or biochemical function.

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

Genes: 1387 207 367 2232 10514

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

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the G101V variant alters the binding affinity of the BCL-2 protein to the drug S55746, indicating a change in molecular function related to drug interaction. Oncogenic: The G101V variant is implicated in the context of tumor development as it affects the binding of a therapeutic agent, suggesting its role in cancer progression.

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

Genes: 596

Variants: E152 E152A G101V V101

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

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the G101V variant alters the binding affinity of the drug S55746, indicating a change in molecular function related to drug interaction. Predictive: The variant G101V is associated with a change in response to the drug S55746, as indicated by the differences in binding affinity and LC50 concentrations, suggesting its role in treatment sensitivity.

Gene→Variant (gene-first): 596:G101V

Genes: 596

Variants: G101V

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

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the E152A mutation alters the binding affinity of the BCL-2 protein to venetoclax, indicating a change in molecular function related to protein binding. Predictive: The evidence suggests that the E152A mutation, when combined with G101V, restores high affinity binding to venetoclax, which implies a correlation with response to this specific therapy.

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

Genes: 596

Variants: E152 E152A G101A G101V

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 8

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses how the BCL-2 mutants, including G101V, F104L, and F104C, exhibit varying affinities for venetoclax, indicating their role in providing resistance to therapy. Functional: The passage describes how the BCL-2 mutants maintain tight binding to BH3 domains, which alters their molecular function and contributes to their ability to prevent apoptosis.

Gene→Variant (gene-first): 596:F104C 596:F104L 596:G101V

Genes: 596

Variants: F104C F104L G101V

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the F104L mutation alters the packing environment of the chlorophenyl moiety of the drug, indicating a change in molecular function related to the variant.

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

Genes: 596

Variants: F104 F104L L104

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

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the G101V mutation alters drug binding by changing the molecular interactions within the BCL-2 structure, indicating an alteration in biochemical function. Predictive: The evidence suggests that the G101V mutation impacts the binding affinity of venetoclax, which correlates with the response to this specific therapy.

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

Genes: 596

Variants: E152 G101 G101A G101V

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 12

Evidence Type(s): Diagnostic, Functional

Justification: Diagnostic: The passage discusses the identification of rare germline variants (V37M, R181H) in patients with B-ALL, indicating their association with the disease. Functional: Luciferase assays performed on the variants showed no significant changes in transcriptional repression activity compared to WT ETV6, indicating an assessment of their molecular function.

Gene→Variant (gene-first): 2120:11905459G>A 2120:12022436 G>A 2120:R181H 2120:V37M 2120:rs150089916

Genes: 2120

Variants: 11905459G>A 12022436 G>A R181H V37M rs150089916

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

Evidence Type(s): Functional

Justification: Functional: The detection of different localization patterns for the mutants P214L, R369Q, and R399C also suggests alterations in their molecular or biochemical function.

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

Genes: 2120

Variants: L349P N385fs P214L R369Q R399C

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the mutations L349P, N385fs, P214L, R369Q, and R399C impair the transcriptional repression function of ETV6, indicating that these variants alter molecular function.

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

Genes: 2120

Variants: L349P N385fs P214L R369Q R399C

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the L349P and N385fs mutations are predicted to alter the molecular function of the ETV6 protein, including conformational changes and truncation that affect DNA interaction.

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

Genes: 2120

Variants: L349P N385fs

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

Evidence Type(s): Predisposing, Functional

Justification: Predisposing: The passage discusses inherited mutations in ETV6 that confer susceptibility to acute leukemia, indicating a germline origin and inherited risk for developing the disease. Functional: The passage describes how the ETV6 mutations (L349P and N385fs) alter the protein's localization and its ability to regulate gene expression, demonstrating a change in molecular function.

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

Genes: 2120

Variants: L349P N385fs

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

Evidence Type(s): Predisposing, Oncogenic, Functional

Justification: Predisposing: The passage describes a germline ETV6 p. L349P mutation identified in a kindred affected by thrombocytopenia and ALL, indicating an inherited risk for developing the disease. Oncogenic: The ETV6 p. N385fs mutation was found in leukemic cells and is associated with the deletion of wild type ETV6, suggesting its contribution to tumor development in the context of leukemia. Functional: The enforced expression of the ETV6 mutants showed impaired nuclear localization and a significantly reduced ability to regulate the transcription of ETV6 target genes, indicating an alteration in molecular function.

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

Genes: 2120

Variants: p. L349P p. N385fs

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the impact of the insertions on the catalytic Gln61 might be stronger, indicating an alteration in molecular function related to GTP hydrolysis.

Gene→Variant (gene-first): 5921:Gln61

Genes: 5921

Variants: Gln61

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the HRAS p.G12V variant alters the signaling capability by affecting GTP hydrolysis and inducing phosphorylation of ERK and AKT, indicating a change in molecular function. Oncogenic: The HRAS p.G12V variant is implicated in inducing signaling pathways that are associated with tumor development, as evidenced by the increased levels of phosphorylated ERK and AKT in the transfected cells.

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

Genes: 3845

Variants: p.G12V

[Paragraph-level] PMCID: PMC6547725 Section: RESULTS PassageIndex: 22

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the classical oncogenic variant KRAS p.G12V in the context of its effect on GTP hydrolysis, indicating its role in tumor development or progression. Functional: The passage describes how the variant KRAS p.G12V affects the biochemical function of GTP hydrolysis, demonstrating its impact on molecular activity in the presence of RAS-GAP.

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

Genes: 3845

Variants: p.G12V

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the p.G12V variant alters the intrinsic GTP hydrolysis rates, indicating a change in molecular function related to protein activity. Oncogenic: The p.G12V variant is described as a classical oncogenic variant, suggesting its role in tumor development or progression.

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

Genes: 3845

Variants: p.G12V

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: KRAS p.G12V is described as a classical oncogenic variant, indicating its contribution to tumor development or progression. Functional: The passage discusses how KRAS p.G12V alters the intrinsic dissociation rate of mGppNHp compared to wild type, indicating a change in molecular function.

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

Genes: 3845

Variants: p.G12V

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the impact of the p.Q61L variant on nucleotide exchange, effector binding, and GTP hydrolysis, indicating that it alters molecular or biochemical function. Oncogenic: The p.Q61L variant is described as a classic pathogenic missense mutation, suggesting its contribution to tumor development or progression.

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

Genes: 4893

Variants: p.Q61L

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the insertions around Gln61 likely alter the molecular interactions and functions of the protein, particularly affecting GTP hydrolysis and interactions with GEFs and GAPs.

Gene→Variant (gene-first): 5921:Gln61

Genes: 5921

Variants: Gln61

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses mutations in RAS genes, including p.G12A, p.G13H, and p.Q22K, which are described as classical oncogenic mutations that affect tumor development and progression. Functional: The passage indicates that the p.Q22K mutation is associated with increased GTP loading, suggesting that it alters molecular function related to protein activity.

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

Genes: 3845

Variants: p.G12A p.G13H p.Q22K

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how several variants, including K131, R168G, G130R, and others, alter the molecular function of RAD51C by disrupting the ATP-binding site and influencing RAD51C activity, as demonstrated in HDR assays. Oncogenic: The passage indicates that the variants are deleterious and influence RAD51C function, which is relevant to tumor development or progression, particularly in the context of HDR assays.

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

Genes: 5889 5892

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

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how various RAD51C variants affect the ability to form protein complexes involved in DNA damage repair, indicating that these variants alter molecular function. Oncogenic: The mention of deleterious variants that lose the ability to form complexes suggests a role in tumor development or progression, as these variants are associated with impaired DNA repair mechanisms.

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

Genes: 5889 5892

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

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how RAD51C variants alter cell proliferation and the formation of RAD51 foci in response to ionizing radiation, indicating changes in molecular function related to DNA damage signaling and repair. Oncogenic: The variants are implicated in a proliferation defect and disruption of homologous recombination (HR) repair, suggesting their role in tumor development or progression.

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

Genes: 5889

Variants: G130R G302V K131I L138F Q133E R168G T132R

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

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the L138F variant alters HDR activity in different cell lines, indicating a change in molecular function. Predictive: The passage mentions the sensitivity of variants, including L138F, to cisplatin and olaparib, suggesting a correlation with response to these therapies.

Gene→Variant (gene-first): 5889:L138F

Genes: 5889

Variants: L138F

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

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the sensitivity of specific RAD51C variants (G130R, K131I, T132R, Q133E, and G302V) to olaparib, indicating a correlation with response to therapy. Functional: The passage describes the introduction of RAD51C variants into a cell line and assesses their effects on homologous recombination repair (HDR), indicating that these variants alter molecular function.

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

Genes: 5889

Variants: G130R G302V K131I L138F Q133E R168G T132R

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

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how RAD51C missense variants alter RAD51 foci formation in response to DNA damage, indicating a change in molecular function related to DNA repair mechanisms. Predictive: The mention of "drug response findings" suggests that the variants may correlate with sensitivity or resistance to a specific therapy, indicating predictive evidence.

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

Genes: 5889 5888

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

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

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the influence of RAD51C missense variants on the response to cisplatin and olaparib, indicating a correlation between the variants and treatment sensitivity. Functional: The passage describes how the variants affect IC50 values in the HDR assay, suggesting that they alter molecular function related to drug response.

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

Genes: 5889

Variants: E94K G306R p.Glu94Lys p.Gly306Arg

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the influence of missense mutations on RAD51C HR DNA repair activity, indicating that the variants alter molecular function as assessed by HDR activity in a cell-based assay. Oncogenic: The mention of deleterious variants categorized based on their impact on HDR activity suggests that these somatic variants contribute to tumor development or progression through their effects on DNA repair mechanisms.

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

Genes: 5889

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

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the transformation ability of JAK1 mutations, specifically noting that JAK1S703I and JAK1S729C are capable of continual proliferation in the absence of IL-3, indicating their contribution to tumor development or progression. Functional: The passage mentions that JAK1S703I activates the JAK-STAT signaling pathway, which indicates an alteration in molecular function related to the variant.

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

Genes: 3716

Variants: E483D S703I S729C

[Paragraph-level] PMCID: PMC4868698 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the introduction of JAK1 mutations, including E483D, S703I, and S729C, alters the expression levels of phosphorylated JAK1 and STAT proteins, indicating a change in molecular function. Oncogenic: The passage mentions that JAK1S729C is a known and recurrent activating mutation, suggesting its role in tumor development or progression.

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

Genes: 3716

Variants: E483D S703I S729C

[Paragraph-level] PMCID: PMC4868698 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage indicates that the S703I mutation is an activating mutation of the JAK1 gene and was found in tumors, suggesting it contributes to tumor development or progression. Functional: The S703I mutation is described as potentially causing disruption of auto-inhibition of the JAK1 kinase, indicating an alteration in molecular or biochemical function.

Gene→Variant (gene-first): 3716:A1086S 3716:E483D 728378:N451S 3716:S703I

Genes: 3716 728378

Variants: A1086S E483D N451S S703I

[Paragraph-level] PMCID: PMC7472556 Section: RESULTS PassageIndex: 12

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses resistance-promoting activity and its correlation with HER3 phosphorylation, indicating a relationship with response or resistance to therapy. Functional: The passage describes how the variant affects HER3 phosphorylation activity, suggesting an alteration in molecular function related to resistance-promoting activity.

Gene→Variant (gene-first): 5979:Q8

Genes: 5979

Variants: Q8

[Paragraph-level] PMCID: PMC4899144 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage describes how the somatic mutations Y641F and Y646F in the EZH2 gene contribute to tumor development, specifically leading to high-penetrance lymphoma and melanoma in a mouse model. Functional: The variant Ezh2Y641F is shown to alter molecular function by increasing global H3K27 trimethylation and causing a redistribution of this mark, which affects transcription at various loci.

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

Genes: 2146

Variants: Y641F Y646F

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The variant c.169A>G results in an amino acid substitution (p.Lys57Glu) that is associated with a gain of function of the MEK1 protein, indicating an alteration in molecular function. Oncogenic: The variant is discussed in the context of its role in the MAP2K1 gene, which is known to contribute to tumor development or progression, suggesting its oncogenic potential.

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

Genes: 5604

Variants: c.169A>G p.Lys57Glu

[Paragraph-level] PMCID: PMC10283448 Section: RESULTS PassageIndex: 14

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses mutations identified in patients who progressed on repotrectinib treatment, suggesting a potential role of these variants in acquired resistance to the therapy. Functional: The passage indicates that further studies are necessary to investigate the functional role of the mutations, implying that these variants may alter molecular or biochemical functions related to resistance mechanisms.

Gene→Variant (gene-first): 1050:196_197insHP 7157:E171G 896:E253Q 2064:H178Q 7157:H179Y 5925:H555R 2064:R143Q

Genes: 1050 7157 896 2064 5925

Variants: 196_197insHP E171G E253Q H178Q H179Y H555R R143Q

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses heterozygous somatic mutations in IDH1, specifically the R132H variant, and its association with tumorigenesis in gliomas, indicating that this variant contributes to tumor development or progression. Functional: The passage mentions that mutations in IDH1, including R132H, cause loss of normal enzyme function and gain-of-function, leading to the accumulation of D-2-hydroxyglutarate, which alters the biochemical function of the enzyme.

Gene→Variant (gene-first): 3417:R132H

Genes: 3417

Variants: R132H

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

Evidence Type(s): Diagnostic, Oncogenic, Functional

Justification: Diagnostic: The passage discusses the identification of the AKT1 (E17K) mutation in various cancer types, indicating its association with melanoma and suggesting its role in defining the presence of this mutation in cancer specimens. Oncogenic: The passage states that the AKT1 E17K mutation is an activating mutation that contributes to tumor development, as evidenced by its identification in melanoma specimens and cell lines, indicating its role in cancer progression. Functional: The passage mentions that the AKT3 E17K mutation results in the activation of AKT when expressed in human melanoma cells, demonstrating a change in molecular function related to the variant.

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

Genes: 207

Variants: AKT1 (E17K E17K

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the lysine-to-methionine mutation at lysine 27 (H3K27M) contributes to tumor development and progression in diffuse midline gliomas, indicating its role as a somatic variant in cancer. Functional: The variant alters molecular function by affecting the levels of proteins in the SWI/SNF complex and influencing chromatin modifications, demonstrating its impact on biochemical processes within the tumor cells.

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

Genes: 3021 55193

Variants: lysine 27 lysine-to-methionine

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage indicates that the homozygous CHEK2 variant p.R474C was contributory to familial cancer, and the inactivation of CHEK2 in mice led to cancers in multiple organs, suggesting a role in tumor development. Functional: The variant p.R474C alters the tertiary structure of the CHK2 protein by disrupting a salt bridge, and subsequent analysis showed that it was unstable and scarcely activated, indicating a change in molecular function.

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

Genes: 11200

Variants: p.R474 p.R474C

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the p.R474C variant alters the molecular function of the CHK2 protein, demonstrating that it is poorly expressed and activated by DNA damage compared to the wild-type protein. Oncogenic: The context implies that the p.R474C variant contributes to tumor development or progression by affecting the function of a cell cycle checkpoint regulator, which is critical in the context of cancer biology.

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

Genes: 11200

Variants: p.R474C

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

Evidence Type(s): Functional

Justification: Functional: The passage indicates that the p.R474C variant affects the activation of the CHK2 protein in response to DNA damage, suggesting an alteration in its molecular function.

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

Genes: 11200

Variants: p.R474C

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variant p.R210 and its substitution p.R210Q relate to the structure and potential function of the protein, indicating that p.R210Q is not likely to affect the function and structure of the protein.

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

Genes: 2217

Variants: p.R210 p.R210Q

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variant p.R474C alters the salt bridge formation and is likely to make the protein unstable, indicating an alteration in molecular function. Oncogenic: The variant p.R474C is described as "disease causing" and likely interferes with protein function, suggesting a role in tumor development or progression.

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

Genes: 11200

Variants: p.R474 p.R474C

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variant p.R474 in CHEK2 was analyzed for its effect on protein function based on evolutionary conservation, indicating that it alters molecular or biochemical function.

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

Genes: 11200

Variants: p.R474

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the deletion of Trp53 in mice and its contribution to tumor development, as evidenced by the increased incidence and earlier onset of tumors in VhlDelta/DeltaTrp53Delta/DeltaRb1Delta/Delta mice compared to other genotypes. Functional: The deletion of Trp53 is described in the context of its role in the p53/G1-S network, indicating that it alters the molecular function related to cell cycle control and tumorigenesis.

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

Genes: 7428

Variants: Trp53 deletion

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the ability of mutant K-Ras proteins to bind to effectors in vitro, indicating that the variants alter molecular interactions, specifically the binding to FLAG-p110alpha. Oncogenic: The mention of K-RasG12D and the other mutant variants in the context of their binding interactions suggests that these somatic variants contribute to tumor development or progression through their altered functional properties.

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

Genes: 5295 3845 5290

Variants: A66dup K-RasG12D Y64G

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the K-RasG12D variant alters the levels of pERK and pAkt, indicating a change in molecular function related to signaling pathways. Oncogenic: The K-RasG12D variant is implicated in modulating effector pathway activation, which suggests its role in tumor development or progression.

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

Genes: 3845

Variants: K-RasG12D

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage describes how the K-RasG12D variant and tandem duplication mutants transform Ba/F3 cells to cytokine-independent growth, indicating their role in tumor development or progression. Functional: The passage mentions that Ba/F3 cells expressing K-RasG12D and the tandem duplication mutants had elevated levels of Ras-GTP, suggesting that these variants alter molecular function related to Ras signaling.

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

Genes: 5295 3845

Variants: A66dup K-RasG12D

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants K-RasG60_A66dup and K-RasE62_A66dup alter the biochemical properties of K-Ras, specifically their GTPase activity and response to GAP stimulation, indicating a change in molecular function. Oncogenic: The variants are described in the context of their role in accumulating in the active GTP conformation and exhibiting impaired GTPase activity, which suggests their contribution to tumor development or progression.

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

Genes: 5295 3845

Variants: A66dup K-RasG12D

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variant Glutamine 61 (Q61) may alter protein-protein interactions and the structural dynamics of Ras, indicating a change in molecular function due to the predicted effects of switch 2 insertions. Oncogenic: The analysis suggests that the alterations in the Ras protein structure, particularly involving Q61, may contribute to the GTP conformation of Ras, which is associated with tumor development and progression.

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

Genes: 3845

Variants: Glutamine 61 Q61

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the K-RasG12D variant induces cytokine-independent colony formation and contributes to abnormal growth patterns in hematopoietic progenitor cells, indicating its role in tumor development. Functional: The variant K-RasG12D alters the growth response of progenitor cells to GM-CSF, demonstrating a change in molecular function related to colony formation.

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

Genes: 5295 3845

Variants: A66dup K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage describes a partial duplication of the K-Ras gene that is associated with juvenile myelomonocytic leukaemia (JMML), indicating that the variant contributes to tumor development or progression. Functional: The immunoblot analysis shows that the variant alters the molecular function of K-Ras, as evidenced by the detection of a band with reduced electrophoretic mobility compared to normal Ras protein, indicating a change in protein behavior.

Gene→Variant (gene-first): 3845:c.178_198dup 3845:c.184_198dup

Genes: 3845

Variants: c.178_198dup c.184_198dup

[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 14

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the response of FGFR3 variants K650M and K650N to FGFR TKIs, indicating their sensitivity to specific therapies, which aligns with predictive evidence. Functional: The passage describes the alteration of phosphorylation status of the FGFR3 variants K650M and K650N in response to treatment, indicating a change in molecular function due to the variants.

Gene→Variant (gene-first): 2261:K650M 2261:K650N

Genes: 2261

Variants: K650M K650N

[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the evaluation of mRNA and protein expression levels of the R248H variant, indicating that it alters protein expression compared to oncogenic variants, which relates to its molecular function. Oncogenic: The passage implies that the R248H variant is classified as a non-oncogenic variant, contrasting it with oncogenic variants, suggesting its role in tumor development or progression is not supported.

Gene→Variant (gene-first): 1956:R248H

Genes: 1956

Variants: R248H

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the acquisition of the SF3B1 R625C, K700E, and SETBP1 E862K mutations during disease evolution, indicating their role in tumor development and progression in the context of MDS-EB transforming to AML. Functional: The mention of the SF3B1 mutations leading to changes in bone marrow morphology, such as the appearance of ring sideroblasts, suggests that these variants alter molecular or biochemical function related to the disease.

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

Genes: 26040 23451

Variants: E862K K700E R625C

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the impact of the SF3B1 K700E variant on alternative splicing events, indicating that it alters molecular function related to splicing and gene expression. Oncogenic: The SF3B1 K700E variant is associated with mutated myelodysplastic syndromes (MDS), suggesting its role in tumor development or progression.

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

Genes: 23451

Variants: K700E

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses splicing analysis related to the K700E variant, indicating an alteration in molecular function.

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

Genes: 23451

Variants: K700E

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses K-Ras mutations identified in tumors, indicating that these variants contribute to tumor development or progression, particularly with reference to their phenotypes in the context of cancer. Functional: The passage describes the phenotypic effects of the K-Ras mutations, suggesting that they alter molecular or biochemical function, as evidenced by the comparison of their phenotypes to hotspot mutations and wild-type K-Ras.

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

Genes: 3845

Variants: Ala146Thr Arg164Gln Leu19Phe Lys117Asn

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how specific amino acid substitutions at G12, G13, and Q61 alter biochemical properties and mechanisms across RAS proteins, indicating a change in molecular function related to GTP hydrolysis and downstream signaling. Oncogenic: The mention of hotspot variants and their clustering patterns suggests that these somatic variants contribute to tumor development or progression, particularly in the context of their distinct biochemical properties and disease incidence.

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

Genes: 3845

Variants: G12 G13 Q61

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how different KRAS mutations, including G12C/D and G12D, affect downstream activity and enzyme function, as demonstrated by Western blot analyses measuring pERK levels. Oncogenic: The mention of KRAS hotspot variants and their distinct effects on downstream signaling suggests that these somatic mutations contribute to tumor development or progression.

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

Genes: 3845

Variants: G12 G12C G12C/D G12D G13 Q61

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

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how specific amino acid substitutions affect RAF affinity, indicating that these variants alter molecular function related to protein interactions. Predictive: The passage predicts changes in RAF affinity for various variants, suggesting a correlation with potential therapeutic responses or resistance based on their affinity levels.

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

Genes: 3265 673 3845 4893 22882

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

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the KRAS variants alter RAF affinity, indicating that these variants affect molecular function, specifically in relation to protein interactions and binding properties. Oncogenic: The context of the variants being associated with RAF affinity suggests a role in tumor development or progression, as RAF is a key component in signaling pathways that drive cancer.

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

Genes: 3845 3265 673 4893 22882

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

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

Evidence Type(s): Functional, Predictive, Oncogenic

Justification: Functional: The passage discusses how mutated KRAS proteins may alter GAP binding and change GAP-mediated hydrolysis rates, indicating that the variants affect molecular function. Predictive: The analysis provides a probability density distribution and suggests that the variants can predict relative levels for mutations based on their GAP-mediated hydrolysis rates, indicating a correlation with functional outcomes. Oncogenic: The context of the variants being associated with cancer and their effects on GAP-mediated hydrolysis suggests that these somatic variants contribute to tumor development or progression.

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

Genes: 3845 3265 673 22882

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

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how mutations, including G13C, A146V, K117N, and G13V, alter local stability and modulate local unfolding, indicating a change in molecular function related to the hydrolysis rate.

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

Genes: 3265 3845

Variants: A146V G13C G13V K117N

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

Evidence Type(s): Functional, Diagnostic

Justification: Functional: The passage discusses how various KRAS variants, including both hotspot and non-hotspot mutations, exhibit distinct profiles and behaviors based on experimental measurements, indicating that these variants alter molecular or biochemical function. Diagnostic: The mention of clustering variants and their association with specific profiles suggests that these variants can be used to classify or define differences in behavior, which aligns with diagnostic evidence.

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

Genes: 3845 3265 673 22882

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

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how various KRAS variants, including G12, G12V, G13, Q61, and T74, affect biochemical properties such as GTP binding, nucleotide exchange, and hydrolysis, indicating that these variants alter molecular or biochemical function.

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

Genes: 3845 22882

Variants: G12 G12V G13 Q61 T74

[Paragraph-level] PMCID: PMC8033310 Section: ABSTRACT PassageIndex: 4

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the establishment of TNBC cell lines with PIK3CA gene mutations (E545K and H1047R) and their use in in vivo experiments, indicating that these somatic variants contribute to tumor development or progression. Functional: The passage mentions the use of various assays (e.g., western blot, quantitative reverse transcription-polymerase chain reaction) to detect gene and protein expression levels, suggesting that the variants may alter molecular or biochemical function.

Gene→Variant (gene-first): 5290:E545K 5290:H1047R

Genes: 5290

Variants: E545K H1047R

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variant C797 interacts with the inhibitor at a molecular level, specifically forming covalent bonds and influencing the binding interactions within the kinase structure.

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

Genes: 1956

Variants: C797 T790

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 17

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the variant T790 interacts with the drug TAK-788, specifically mentioning hydrogen bonding and binding modes, indicating an alteration in molecular function. Predictive: The mention of TAK-788 binding to T790 suggests a correlation with therapeutic response, as it implies that the presence of T790 may influence the effectiveness of the treatment.

Gene→Variant (gene-first): 1956:T790

Genes: 1956

Variants: T790

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the C797 variant forms a covalent bond with the inhibitor, indicating an alteration in molecular function related to drug binding. Oncogenic: The T790M and V948R variants are described in the context of adopting an inactive kinase conformation, which suggests their role in tumor progression or development.

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

Genes: 1956

Variants: C797 T790M V948R

[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the measurement of biochemical potencies of EGFR inhibitors against specific mutants, including L858R and L858R/T790M, indicating a correlation with response to therapy. Functional: The passage describes the use of recombinant EGFR kinase proteins in assays to evaluate the biochemical activity of inhibitors, which implies that the variants may alter molecular function.

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

Genes: 1956

Variants: L858R T790M

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses enzyme kinetic parameters and catalytic efficiencies of the L858R variant and other variants, indicating that these variants alter molecular function as demonstrated by the enzyme assays.

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

Genes: 7294 1956

Variants: Glu4 L858R T790M

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the S310F variant of HER2 interacts with EGFR and compares its efficiency to wild-type HER2, indicating an alteration in molecular function.

Gene→Variant (gene-first): 2064:S310F

Genes: 2064

Variants: S310F

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the interaction of the S310F HER2 mutant with EGFR and its altered reactivity to specific antibodies, indicating a change in molecular function. Oncogenic: The S310F HER2 variant is implicated in altered interactions that may contribute to tumor development or progression, as suggested by the context of the study involving cancer-related proteins.

Gene→Variant (gene-first): 2064:S310F

Genes: 2064

Variants: S310F

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

Evidence Type(s): Functional

Justification: Functional: The passage indicates that the S310F variant alters the molecular interaction by forming heterodimers with EGFR, suggesting a change in biochemical function.

Gene→Variant (gene-first): 2064:S310F

Genes: 2064

Variants: S310F

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the expression of the S310F HER2 mutant and its interaction with pertuzumab, indicating that the variant alters the molecular function of HER2 in terms of immunoprecipitation. Oncogenic: The S310F variant is described in the context of its expression in cancer cell lines, suggesting that it may contribute to tumor development or progression.

Gene→Variant (gene-first): 2064:S310F

Genes: 2064

Variants: S310F

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the expression and detection of the S310F HER2 mutant in a bladder cancer cell line, indicating that the variant alters the molecular function of the HER2 protein as it is being analyzed for its presence on the cell surface. Oncogenic: The S310F variant is discussed in the context of a bladder cancer cell line, suggesting that it may contribute to tumor development or progression, which aligns with the definition of an oncogenic variant.

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

Genes: 2064

Variants: S310 S310F

[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 3

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the binding interactions of various HER2 mutants with the antibodies pertuzumab and trastuzumab, indicating their response to these therapies. Functional: The passage describes the preparation and purification of recombinant fusion proteins and their binding characteristics, which suggests alterations in molecular function related to the HER2 mutants.

Gene→Variant (gene-first): 2064:G309 2064:G309A 2064:G309E 2064:S309A 2064:S310 2064:S310F 2064:S310Y

Genes: 2064

Variants: G309 G309A G309E S309A S310 S310F S310Y

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

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage indicates that the S310F mutant is not reactive to Pertuzumab, suggesting a correlation with resistance to this specific therapy. Functional: The passage discusses the binding characteristics of the S310F mutant, indicating an alteration in molecular function related to its interaction with Trastuzumab.

Gene→Variant (gene-first): 2064:S310F

Genes: 2064

Variants: S310F

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

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the sensitivity of the V769dupASV variant to 2nd generation EGFR TKIs, indicating a correlation with response to therapy. Functional: The variant V769dupASV is shown to alter the biochemical function of EGFR, as evidenced by the differing levels of inhibition of phosphorylated EGFR in response to dacomitinib.

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

Genes: 1956

Variants: V769dupASV

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

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the expected efficacy of the JNJ42756493 inhibitor towards the FGFR3 V555M variant, indicating a correlation with response to therapy based on structural interactions. Functional: The passage mentions the interactions of inhibitors within the ATP-binding pocket of the FGFR1 KD V561M variant, suggesting that the variant alters molecular function related to drug binding and efficacy.

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

Genes: 2261 2260

Variants: V555M V561M

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

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses how specific mutations, such as K650E, N540K, N540S, and V555M, affect the efficacy of various inhibitors, indicating a correlation with resistance or sensitivity to therapy. Functional: The passage describes how mutations like I538V and V555M alter the binding affinity and efficacy of inhibitors, which reflects changes in molecular function related to drug interactions.

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

Genes: 2263 2261

Variants: I538 I538V K650E N540 N540K N540S R669G V555M

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

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the Ki values of various FGFR3 variants in response to specific inhibitors, indicating a correlation between the variants and their sensitivity to therapy. Functional: The mention of mutations affecting the ATP binding pocket and potential allosteric effects suggests that these variants alter the molecular function of the FGFR3 protein.

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

Genes: 2263 2261

Variants: I538V K650E N540K N540S R669G V555M

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variants D641, L630, and V561 are involved in the binding interactions of the drug JNJ42756493 with FGFR1, indicating that these variants alter molecular interactions and contribute to the binding strength and specificity of the drug.

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

Genes: 2260

Variants: D641 L630 V561

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the K650E, R675G, and R669G mutations alter the allosteric communication and molecular interactions within the FGFR kinases, indicating a change in molecular function. Oncogenic: The mention of mutations that force an active conformation and alter the position of the alphaC-helix suggests that these variants contribute to tumor development or progression.

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

Genes: 2261 2260

Variants: K650E R669G R675 R675G

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the R669G mutation alters molecular interactions and conformational changes in the FGFR3 protein, indicating an alteration in biochemical function.

Gene→Variant (gene-first): 2261:R669G

Genes: 2261

Variants: R669G

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

Evidence Type(s): Functional

Justification: Functional: The passage describes how the R675G variant alters the molecular interactions and conformation of the FGFR1 kinase domain, indicating a change in biochemical function.

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

Genes: 2261 2260 2263

Variants: H650 R675 R675G Y653

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the R to G replacement and its impact on the activity of the FGFR1 KD variant, indicating that the variant alters molecular function. Oncogenic: The mention of the R669 and R675G variants being mutated in cancer suggests their contribution to tumor development or progression.

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

Genes: 2260 2261

Variants: R to G R669 R675G

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses the activation mechanism of the FGFR3 R669G mutation, indicating that it alters molecular or biochemical function.

Gene→Variant (gene-first): 2261:R669G

Genes: 2261

Variants: R669G

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants E466K, D617G, and G637W are predicted to reduce protein production or completely inactivate the kinase, indicating an alteration in molecular function. Oncogenic: The mention of R669 being within an identified cluster of observed A-loop cancer mutations suggests that it contributes to tumor development or progression.

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

Genes: 2261 2263 2260

Variants: D617G E466K G637W R669

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the R669G variant alters downstream signaling and FGFR3 phosphorylation, indicating a change in molecular function.

Gene→Variant (gene-first): 2261:R669G

Genes: 2261

Variants: R669G

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the G697C mutation does not affect kinase activity directly as measured in vitro, indicating that it alters molecular function, specifically FGFR3 function, which can only be detected in a cellular setting. Oncogenic: The comparison of the FGFR3 G697C cell line with those expressing K650E and N540K shows that G697C does not lead to a transformed phenotype or anchorage-independent growth, suggesting it does not contribute to tumor development or progression like the other variants.

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

Genes: 2261

Variants: G697C K650E N540K

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the K650E variant alters kinase activity, indicating a change in molecular function related to activation. Oncogenic: The mention of the K650E variant in the context of kinase activation suggests its potential role in tumor development or progression.

Gene→Variant (gene-first): 2261:K650E

Genes: 2261

Variants: K650E

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the mutations D617G and G637W abolish kinase activity, indicating that these variants alter the molecular function of the protein. Oncogenic: The passage mentions that the importance of these inactivating mutations for cancer development remains unclear, suggesting a potential role in tumor development or progression.

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

Genes: 2261 2260

Variants: D617 D617G G to W G637 G637W

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the effect of the G697C mutation on FGFR3 KD activity, indicating that it alters molecular function. Oncogenic: The mention of G697C as one of the hotspots suggests its potential role in tumor development or progression, which aligns with oncogenic behavior.

Gene→Variant (gene-first): 2261:G697C

Genes: 2261

Variants: G697C

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

Evidence Type(s): Predictive, Functional

Justification: Predictive: The V555M mutation is described as an acquired resistance mutation to an FGFR inhibitor, indicating a correlation with resistance to therapy. Functional: The passage discusses how the mutations, including V555M, D641G, and D641N, resulted in an increase in auto-phosphorylation and substrate phosphorylation, indicating an alteration in molecular function.

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

Genes: 2260 2261

Variants: D641G D641N V555 V555M

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how different mutations in FGFR3 KD variants affect auto-phosphorylation and kinase activity, indicating that these variants alter molecular function. Oncogenic: The context of the passage suggests that the mutations contribute to tumor development or progression by enhancing kinase activity, which is a characteristic of oncogenic variants.

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

Genes: 2263 2261

Variants: I538V K650E K650N N540K N540S R669G R669Q

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses the functional impact of mutations at positions FGFR3 K650 and N540K, indicating that these variants are assessed for their effect on kinase activity.

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

Genes: 2261

Variants: K650 N540K

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses frequently mutated positions in FGFR3, specifically K650, G697, and N540, indicating their involvement in cancer, which suggests they contribute to tumor development or progression. Functional: The passage describes the specific amino acid replacements at the mutated positions, indicating alterations in molecular function related to FGFR3, which can affect its activity in cancer.

Gene→Variant (gene-first): 2261:G697 2261:G697C 2261:K650 2261:N540

Genes: 2261

Variants: G697 G697C K650 N540

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

Evidence Type(s): Functional, Diagnostic

Justification: Functional: The passage discusses how the ETV6 mutants (V345fs, N356fs, Y103fs, S105fs) are functionally inactive and lack transcriptional repression activity, indicating that these variants alter molecular function. Diagnostic: The passage mentions that ETV6-mutated cases have a characteristic gene expression signature and that all ETV6 mutant T-ALL samples were CD33 positive, suggesting that these variants are associated with a specific disease subtype.

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

Genes: 2120

Variants: N356fs S105fs V345fs Y103fs

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage describes how N-terminal and C-terminal truncating mutations in the ETV6 gene alter the expression of truncated protein products, indicating a change in molecular function. Oncogenic: The context of the mutations being associated with hematopoietic tumors suggests that these somatic variants contribute to tumor development or progression.

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

Genes: 2120

Variants: N356fs S105fs V345fs Y103fs

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

Evidence Type(s): Diagnostic, Functional

Justification: Diagnostic: The passage discusses the identification of a de novo missense variant in ELOC and its validation in the proband, indicating its potential role in defining or confirming a genetic condition. Functional: The passage describes the critical role of the Tyr79 residue in forming a hydrogen bond within the pVHL alpha domain, suggesting that the variant alters molecular function.

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

Genes: 3091

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

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variant H1047L alters the lipid binding capabilities of the p110alpha isoform, indicating a change in molecular function.

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

Genes: 5290

Variants: H1047 H1047L

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the H1047R variant leads to a global conformational change in the p110alpha/p85alpha structure, suggesting that it alters molecular function and potentially impacts activity. Oncogenic: The context implies that the H1047R variant contributes to tumor development or progression through its role in altering the conformational dynamics of the kinase, which is relevant in cancer biology.

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

Genes: 5290

Variants: H1047R

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variants C420R and N564D alter the molecular interactions within the C2 domain, suggesting changes in lipid binding capabilities, which indicates an alteration in biochemical function.

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

Genes: 5290 5295

Variants: C420 C420R E545K N345 N564 N564D

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variants G1049R, H1047L, and H1047R alter binding properties to lipids, indicating a change in molecular function related to lipid binding upon activation.

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

Genes: 5290

Variants: G1049R H1047L H1047R

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the mutations (C420R, E545K, and N564D) alter the hydrophobic interaction with neutral lipids, indicating a change in molecular function related to lipid binding.

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

Genes: 5290 5295

Variants: C420R E545K N564D

[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 17

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the E545K variant alters lipid kinase activity and lipid binding, indicating a change in molecular function.

Gene→Variant (gene-first): 5290:E545K

Genes: 5290

Variants: E545K

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the K942Q and R949D variants alter molecular function, specifically their effects on kinase activity and lipid binding, indicating changes in biochemical properties.

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

Genes: 5294

Variants: K942Q R949D

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the D915N mutation in the context of its role in lipid binding and activation of p110alpha, indicating that it alters molecular function related to protein activity. Oncogenic: The mention of "cancer-linked mutations" suggests that the D915N variant is associated with tumor development or progression, as it is discussed in the context of p110alpha, which is implicated in cancer.

Gene→Variant (gene-first): 5290:D915N

Genes: 5290

Variants: D915N

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the deletion of residues 1051-1068 alters the lipid kinase activity and ATPase activity of p110alpha, indicating a change in molecular function.

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

Genes: 5290

Variants: deletion of residues 1051-1068

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the oncogenic mutant H1047R p110alpha, indicating that this variant is associated with tumor development or progression, particularly in the context of its structural characteristics compared to the wild-type. Functional: The passage describes how the H1047R variant affects the conformation of the C-terminal tail and its interactions, suggesting alterations in molecular or biochemical function related to the protein's structure.

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

Genes: 5290

Variants: H1047R

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses key conserved activation loop residues K942 and R949 and their importance in recognizing the substrate, indicating that these variants alter molecular function related to substrate binding.

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

Genes: 5294

Variants: K942 R949

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

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the D835H mutation's resistance to type II inhibitors, indicating a correlation with treatment response and sensitivity to specific therapies. Functional: The passage describes how the D835H mutation alters the binding mode and hydrogen bond formation, indicating a change in molecular function related to inhibitor interaction.

Gene→Variant (gene-first): 2322:D835H

Genes: 2322

Variants: D835H

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the D835Y/V variant alters molecular interactions and structural compatibility, indicating a change in biochemical function related to steric hindrance and hydrogen bonding. Oncogenic: The mention of "highly resistant mutants" suggests that the D835Y/V variant contributes to tumor development or progression by conferring resistance, which is characteristic of oncogenic behavior.

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

Genes: 2322

Variants: D835Y/V

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

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the D835E/N mutations alter molecular interactions, specifically the formation of hydrogen bonds and the conservation of the alpha-helix structure, which affects inhibitor binding. Predictive: The passage indicates that the D835E/N variants are associated with sensitivity to type II inhibitors, suggesting a correlation with treatment response.

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

Genes: 2322

Variants: D835 D835E/N

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

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the correlation of D835 mutations with resistance to type II inhibitors, indicating a relationship between the variant and treatment response. Functional: The passage describes the impact of D835 mutations on the short alpha-helix and its potential effect on the drug-binding site, suggesting an alteration in molecular function related to drug interaction.

Gene→Variant (gene-first): 2322:D835

Genes: 2322

Variants: D835

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the D835 variant alters the molecular function of the kinase by stabilizing the DFG-out conformation and forming interactions that affect the structure of the alpha-helix.

Gene→Variant (gene-first): 2322:D835

Genes: 2322

Variants: D835

[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how damaging mutations in BTG1, including the p.Q36H and p.E46K variants, may provide a survival advantage to CLL cells under targeted BCL2-inhibition, indicating their contribution to tumor development or progression. Functional: The passage mentions that BTG1 has been shown to counteract cell proliferation, suggesting that the mutations may alter its molecular or biochemical function.

Gene→Variant (gene-first): 7157:p.E46K 694:p.Q36H

Genes: 7157 694

Variants: p.E46K p.Q36H

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

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses the phosphorylation levels of proteins in relation to the HER2V777L mutation, indicating that the variant alters molecular function, specifically in signaling pathways related to cancer. Predictive: The mention of increased phosphorylation of annexin A2 being associated with drug resistance suggests a correlation between the HER2V777L variant and resistance to therapy.

Gene→Variant (gene-first): 2064:V777L

Genes: 2064

Variants: V777L

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the HER2V777L variant enhances cell proliferation by altering the phosphorylation of key proteins involved in the cell cycle, indicating a change in molecular function. Oncogenic: The evidence suggests that the HER2V777L variant contributes to tumor development and progression by promoting aggressive growth in the transgenic mouse model.

Gene→Variant (gene-first): 2064:V777L

Genes: 2064

Variants: V777L

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the HER2V777L mutation's role in metastatic breast cancer, indicating that it contributes to tumor development and progression, particularly in the context of lung metastasis observed in transgenic mice. Functional: The passage implies that the HER2V777L mutation alters the behavior of breast tumor cells, as evidenced by the invasive phenotype observed in vitro and the specific uptake of the NIR-trastuzumab imaging agent in tumor sites.

Gene→Variant (gene-first): 2064:V777L

Genes: 2064

Variants: V777L