[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: 7

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses FGFR3 cancer mutations, indicating that the variants K650, R669, N540, and I538 are associated with cancer, suggesting their role in tumor development or progression.

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

Genes: 2263 2261

Variants: I538 K650 N540 R669

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 6

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 2261:G697 2263:I538 2261:K650 2261:N540 2261:R669

Genes: 2261 2263

Variants: G697 I538 K650 N540 R669

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses mutations in FGFR3, including K650 and N540, in the context of developmental syndromes such as bone dysplasia, indicating their association with specific disease states. Oncogenic: The mention of FGFR3 mutations, including K650 and N540, being prevalent in bladder cancer suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 2261:K650 2261:N540 2261:N540K

Genes: 2261

Variants: K650 N540 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: 9

Evidence Type(s): Oncogenic, Diagnostic

Justification: Oncogenic: The passage describes the NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) variant as a somatic variant found in renal cell carcinomas (RCCs) and indicates its role in VHL-independent renal tumorigenesis, supporting its contribution to tumor development. Diagnostic: The passage discusses the search for germline ELOC variants in individuals with a VHL-like phenotype and indicates that the NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) variant was absent in these individuals, suggesting its potential use in defining or excluding a disease or subtype.

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

Genes: 3091 6921 5979 3855 7409

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

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 8

Evidence Type(s): None

Justification: Not enough information in this passage.

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

Genes: 3091

Variants: c.236A>G p.Tyr79Cys

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

Evidence Type(s): None

Justification: Not enough information in this passage.

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

Genes: 3091

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

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

Evidence Type(s): 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: PMC7325368 Section: RESULTS PassageIndex: 11

Evidence Type(s): Predictive, Diagnostic, Oncogenic

Justification: Predictive: The passage discusses the confirmed responses and stable disease (SD) in patients with K-RAS mutations, including G13D, indicating a correlation with treatment response. Diagnostic: The mention of K-RAS mutations, including G13D, in the context of specific cancer types (endometrial cancer and NSCLC) suggests its role in classifying or defining these diseases. Oncogenic: The reference to K-RAS mutations, including G13D, contributing to tumor development in specific cancer types supports the classification of this variant as oncogenic.

Gene→Variant (gene-first): 3845:G13D

Genes: 3845

Variants: G13D

[Paragraph-level] PMCID: PMC7325368 Section: RESULTS PassageIndex: 10

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the responses of patients with B-RAF mutations to therapy, indicating a correlation between the B-RAFV600E variant and treatment response, which is characteristic of predictive evidence. Oncogenic: The B-RAFV600E variant is mentioned in the context of patients with B-RAF-mutated tumors, suggesting its role in tumor development or progression, which aligns with oncogenic evidence.

Gene→Variant (gene-first): 673:B-RAFV600E

Genes: 673

Variants: B-RAFV600E

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

Evidence Type(s): None

Justification: Not enough information in this passage.

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

Genes: 7010 3845

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

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

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The variant p.L1363P is shown to disrupt the interaction with PALB2 and leads to the development of mammary tumors, indicating its contribution to tumor development. Predictive: The passage states that Brca1 p.L1363P mammary tumors are responsive to cisplatin and PARP inhibition, suggesting a correlation with treatment response.

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

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7302243 Section: RESULTS PassageIndex: 3

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the acquired T790M mutation in the context of EGFR-TKI resistance, indicating a correlation with treatment resistance. Oncogenic: The T790M mutation is described as contributing to EGFR-TKI resistance, which is a characteristic of tumor progression in the context of cancer.

Gene→Variant (gene-first): 1956:T790M

Genes: 1956

Variants: T790M

[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: 16

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses mutations that are characterized as activating, indicating that they contribute to tumor development or progression.

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

Genes: 5290 5295

Variants: C420R E545K G1049R H1047L H1047R M1043I N564D

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses somatic missense mutations in PIK3CA that contribute to increased kinase activities and lipid binding, indicating their role in tumor development or progression. Functional: The passage describes how specific mutations alter the molecular function of the p110alpha protein, including increased basal activity and lipid binding, which are indicative of changes in biochemical function.

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

Genes: 5290 5295

Variants: C420R E545K G1049R H1047L H1047R M1043I N564D

[Paragraph-level] PMCID: PMC4239128 Section: RESULTS PassageIndex: 2

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the potential vulnerability of the malignancy to BRAF inhibition, indicating a correlation between the BRAF p.V600E mutation and response to therapy with dabrafenib and trametinib. Oncogenic: The BRAF p.V600E mutation is implicated in the malignancy's development and progression, as it is associated with the treatment approach and the observed tumor response to therapy.

Gene→Variant (gene-first): 673:1799T > A 673:p.V600E

Genes: 673

Variants: 1799T > A p.V600E

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

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the sensitivity of D835 mutants to type II inhibitors, indicating a correlation with treatment response, which aligns with predictive evidence. Oncogenic: The mention of D835 mutations and their role in mediating resistance and sensitivity to FLT3 TKIs suggests that these somatic variants contribute to tumor development or progression.

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

Genes: 2322

Variants: D835 D835N/E

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

Evidence Type(s): Predictive, Functional

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: PMC4675689 Section: RESULTS PassageIndex: 2

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how various D835 substitutions correlate with resistance to FLT3 inhibitors, indicating their predictive value regarding treatment response. Oncogenic: The D835 mutations are reported to cause resistance in patients, suggesting that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 2322:D835 2322:D835A/E 2322:D835H 2322:D835V/Y

Genes: 2322

Variants: D835 D835A/E D835H D835V/Y

[Paragraph-level] PMCID: PMC4411002 Section: RESULTS PassageIndex: 16

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the identification of PIK3CA mutations in patients with a clinical diagnosis of FAO, indicating that these variants are used to define or confirm the disease in these patients. Oncogenic: The PIK3CA mutations mentioned are somatic variants identified in primary fibroblasts, which suggests they contribute to tumor development or progression in the context of the patients' disease.

Gene→Variant (gene-first): 5294:3140 A>T 5290:c.3140 A>G 5290:c.3140 A>T 5290:p.H1047L 5290:p.H1047R

Genes: 5294 5290

Variants: 3140 A>T c.3140 A>G c.3140 A>T p.H1047L p.H1047R

[Paragraph-level] PMCID: PMC4411002 Section: RESULTS PassageIndex: 15

Evidence Type(s): Diagnostic

Justification: Diagnostic: The passage confirms the presence of the c.241 G>A [p.E81K] mutation in the biopsies of a patient, indicating its role in defining or confirming the disease in that individual.

Gene→Variant (gene-first): 5290:c.241 G>A 5290:p.E81K

Genes: 5290

Variants: c.241 G>A p.E81K

[Paragraph-level] PMCID: PMC4411002 Section: RESULTS PassageIndex: 12

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the identification of the c.241 G>A [p.E81K] mutation in a specific patient, indicating its association with the patient's condition and its absence in the patient's parents, which suggests its role in defining or confirming a disease. Oncogenic: The mention of the mutation being detected in various tissues of the patient, particularly in the context of a mutational analysis, implies its potential contribution to tumor development or progression.

Gene→Variant (gene-first): 5290:c.241 G>A 5290:p.E81K

Genes: 5290

Variants: c.241 G>A p.E81K

[Paragraph-level] PMCID: PMC12221223 Section: RESULTS PassageIndex: 3

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the identification of mutational profiles in melanoma, specifically mentioning that C>T transitions are characterized as cutaneous melanoma-defining features, which indicates a role in classifying or defining the disease. Oncogenic: The mention of C>T transitions as part of the mutational profile in melanoma suggests that these somatic variants contribute to tumor development or progression, particularly in the context of melanoma.

Gene→Variant (gene-first): 4763:C>T

Genes: 4763

Variants: C>T

[Paragraph-level] PMCID: PMC8077124 Section: ABSTRACT PassageIndex: 10

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The variant p.K656E is described as an activating and transforming mutation, indicating its role in tumor development or progression. Predictive: The variant p.V561M is mentioned as imparting resistance to FGFR inhibitors, suggesting its correlation with treatment response.

Gene→Variant (gene-first): 2260:p.K656E 2260:p.V561M

Genes: 2260

Variants: p.K656E p.V561M

[Paragraph-level] PMCID: PMC8077124 Section: ABSTRACT PassageIndex: 9

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the potential use of FGFR inhibitors in combination with other treatments, indicating a correlation with therapy response. Oncogenic: The mention of mutations in the context of a tumor suggests that the variants may contribute to tumor development or progression.

Gene→Variant (gene-first): 2260:p.K656E 2260:p.V561M

Genes: 2260

Variants: p.K656E p.V561M

[Paragraph-level] PMCID: PMC8077124 Section: ABSTRACT PassageIndex: 7

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The passage describes p.K656E as a known hotspot mutation that is activating and transforming, indicating its role in tumor development or progression. Predictive: The passage mentions that p.V561M is described as a gatekeeper mutation imparting resistance to FGFR inhibitors, which correlates with treatment response.

Gene→Variant (gene-first): 2260:p.K656E 2260:p.V561M

Genes: 2260

Variants: p.K656E p.V561M

[Paragraph-level] PMCID: PMC4741605 Section: RESULTS PassageIndex: 20

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of the patient to chemotherapy treatment and how the presence of the D835Y mutation correlates with the patient's relapse, indicating its potential role in therapeutic decisions. Oncogenic: The D835Y mutation is described as a mutation that contributes to the tumor's behavior, particularly in the context of the patient's relapse and the increase in the mutated clone's percentage.

Gene→Variant (gene-first): 2322:D835Y

Genes: 2322

Variants: D835Y

[Paragraph-level] PMCID: PMC4741605 Section: RESULTS PassageIndex: 19

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the resistance of the D835Y variant to conventional induction chemotherapy and indicates that the treatment successfully inhibited the D835Y mutated clone, suggesting a correlation with treatment response. Oncogenic: The D835Y variant is mentioned in the context of tumor progression and its behavior in response to treatment, indicating its role in tumor development or progression.

Gene→Variant (gene-first): 2322:D835Y

Genes: 2322

Variants: D835Y

[Paragraph-level] PMCID: PMC4741605 Section: RESULTS PassageIndex: 18

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage states that the mutations D839G and D835H are able to confer resistance to Sorafenib treatment, indicating a correlation between these variants and treatment response. Oncogenic: The presence of the D839G and D835H mutations is associated with the evolution of the FLT3 ITD+ clone and suggests a role in tumor development or progression, particularly in the context of acute myeloid leukemia (AML).

Gene→Variant (gene-first): 2322:D835H 2322:D839G

Genes: 2322

Variants: D835H D839G

[Paragraph-level] PMCID: PMC4741605 Section: RESULTS PassageIndex: 17

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the patient's response to the FLT3 inhibitor AC220-002, indicating that the presence of the D835Y and D839G variants may correlate with the patient's treatment response. Oncogenic: The D835Y and D839G variants are mentioned in the context of their abundance in the patient's sample, suggesting their potential role in tumor development or progression as part of the FLT3 mutation landscape.

Gene→Variant (gene-first): 2322:D835Y 2322:D839G

Genes: 2322

Variants: D835Y D839G

[Paragraph-level] PMCID: PMC9398166 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how the G1202R and L1196M mutations are major resistance mechanisms to ALK inhibitors, indicating that these variants correlate with resistance to specific therapies. Oncogenic: The G1202R and L1196M mutations are described as resistance mechanisms that contribute to tumor progression, particularly in the context of ALK inhibitors, suggesting their role in oncogenesis.

Gene→Variant (gene-first): 238:G1202R 238:L1196M

Genes: 238

Variants: G1202R L1196M

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 12

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the correlation of TPX-0131 treatment with tumor growth inhibition and suppression of ALK phosphorylation, indicating that the G1202R, L1196M, and L1198F variants are associated with resistance to therapy and response to treatment. Oncogenic: The variants G1202R, L1196M, and L1198F are described in the context of ALK resistance mutations, suggesting their role in tumor development or progression as they are associated with the EML4-ALK fusion in a cancer model.

Gene→Variant (gene-first): 238:G1202R 238:L1196M 238:L1198F

Genes: 238

Variants: G1202R L1196M L1198F

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 11

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of tumor models harboring specific ALK mutations (G1202R, L1196M, L1198F) to the therapy TPX-0131, indicating a correlation between the variants and treatment efficacy. Oncogenic: The variants G1202R, L1196M, and L1198F are described in the context of tumor models, suggesting that they contribute to tumor development or progression as part of the EML4-ALK fusion.

Gene→Variant (gene-first): 238:G1202R 238:L1196M 238:L1198F

Genes: 238

Variants: G1202R L1196M L1198F

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how the variants G1202R, L1196M, and L1198F correlate with the response to the ALK inhibitor TPX-0131, indicating their role in resistance to therapy. Oncogenic: The variants mentioned are part of ALK oncogenic fusion proteins, which are implicated in tumor development and progression, as evidenced by their evaluation in assays measuring ALK autophosphorylation.

Gene→Variant (gene-first): 238:G1202R 238:L1196M 238:L1198 238:L1198F

Genes: 238

Variants: G1202R L1196M L1198 L1198F

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 8

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of the ALK G1202R/G1269A/L1204V triple mutation to the TPX-0131 inhibitor, indicating a correlation with treatment sensitivity. Oncogenic: The mention of the EML4-ALK compound mutations, including G1202R, G1269A, and L1204V, in the context of cell proliferation assays suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 238:G1202R 238:G1269A 238:L1204V

Genes: 238

Variants: G1202R G1269A L1204V

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the potency of TPX-0131 against various ALK mutations, indicating that the variant mutations correlate with the response to the therapy, specifically highlighting the differences in inhibition potency against different mutations. Oncogenic: The passage describes the use of engineered Ba/F3 cells expressing oncogenic EML4-ALK variants, indicating that these mutations contribute to tumor development or progression, as they are associated with resistance to ALK inhibitors.

Gene→Variant (gene-first): 238:C1156Y 238:G1202R 238:G1269A 238:G1269S 238:I1171N 238:I1171N/S 238:L1196M 238:L1198F 238:L1204V 238:S/T

Genes: 238

Variants: C1156Y G1202R G1269A G1269S I1171N I1171N/S L1196M L1198F L1204V S/T

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 5

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the potency of TPX-0131 against various ALK mutations, indicating its effectiveness as a therapy for these specific variants, which correlates with treatment response. Functional: The passage describes the biochemical characterization of TPX-0131's inhibition of ALK mutations, focusing on its molecular properties and binding interactions that alter the function of the ALK protein.

Gene→Variant (gene-first): 238:C1156Y 238:D1203N 238:E1210K 238:F1174C 238:F1174L 238:F1174S 238:F1245C 238:G1202 238:G1202R 238:G1269A 238:G1269S 238:I1171N 238:L1152P 238:L1152R 238:L1196M 238:L1198F 238:R1275Q 238:S1206C 238:S1206R 238:T1151-L1152 insT 238:T1151M 238:V1180L

Genes: 238

Variants: C1156Y D1203N E1210K F1174C F1174L F1174S F1245C G1202 G1202R G1269A G1269S I1171N L1152P L1152R L1196M L1198F R1275Q S1206C S1206R T1151-L1152 insT T1151M V1180L

[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 3

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses resistance mutations, including G1202, in the context of second-generation ALK inhibitors and their reduced potency, indicating a correlation with treatment response. Oncogenic: The mention of G1202 as a resistance mutation suggests that it contributes to tumor development or progression by obstructing binding and reducing the efficacy of ALK inhibitors.

Gene→Variant (gene-first): 238:G1202

Genes: 238

Variants: G1202

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

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how the BRAFV600E variant correlates with venetoclax resistance, indicating a relationship between the variant and treatment response. Oncogenic: The passage describes the overexpression of the mutated BRAF (p.V600E) in a cell line, which is associated with increased resistance to venetoclax, suggesting that this somatic variant contributes to tumor progression.

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

Genes: 673 7157

Variants: BRAFV600E p.V600E p.W110*

[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 14

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the SF3B1 mutations in the context of venetoclax exposure and resistance, indicating a correlation between these variants and treatment response. Oncogenic: The SF3B1 mutations are described as evolving during treatment and being selected for during venetoclax therapy, suggesting their role in tumor development or progression.

Gene→Variant (gene-first): 23451:c.1996A > C 23451:c.1997A > C 23451:p.K666Q 23451:p.K666T

Genes: 23451

Variants: c.1996A > C c.1997A > C p.K666Q p.K666T

[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 13

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the selection of specific mutations (including p.K601E and p.Q547fs) during venetoclax therapy, indicating a correlation with treatment response. Oncogenic: The mutations p.K601E and p.S321fs are described as contributing to tumor development, as they are retained in the clonal evolution of the cancer during relapse.

Gene→Variant (gene-first): 673:p.K601E 330:p.Q547fs 58508:p.S321fs

Genes: 673 330 58508

Variants: p.K601E p.Q547fs p.S321fs

[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 12

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the involvement of BTG1 mutations (p.E46K and p.Q36H) in the resistance to venetoclax treatment, indicating a correlation between these variants and treatment response. Oncogenic: The passage describes the BTG1 mutations as being involved in the clonal evolution towards therapy resistance, suggesting that these somatic variants contribute to tumor development or progression.

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

Genes: 7157 694

Variants: p.E46K p.Q36H

[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: PMC5820258 Section: RESULTS PassageIndex: 8

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The passage states that the BRAF (p.K601E) mutation was shown to be oncogenic and can be targeted by MEK inhibitors, indicating its role in tumor development or progression. Predictive: The mention of patients responding to venetoclax therapy, even with the presence of the BRAF mutation, suggests a correlation with treatment response, which aligns with predictive evidence.

Gene→Variant (gene-first): 673:p.K601E

Genes: 673

Variants: p.K601E

[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 25

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the association of the H1047R PIK3CA mutation with specific tumor subtypes, indicating its role in classifying or defining disease characteristics in human samples. Oncogenic: The H1047R PIK3CA mutation is mentioned in the context of tumor analysis, suggesting its contribution to tumor development or progression as it is examined alongside other mutations in cancer samples.

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

Genes: 5290

Variants: H1047R

[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 22

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage indicates that the co-expression of the HER2V777L variant contributes to tumorigenesis by amplifying signaling pathways, suggesting its role in tumor development.

Gene→Variant (gene-first): 2064:V777L

Genes: 2064

Variants: V777L

[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 20

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 2064:V777L

Genes: 2064

Variants: V777L

[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: 15

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of the WHIM51 PDX model to the drug combination of neratinib plus T-DXd, indicating that the G776insYVMA and V777L mutations correlate with a significant tumor regression in response to this therapy. Oncogenic: The G776insYVMA and V777L mutations are associated with tumor regression in the context of breast cancer, suggesting that these somatic variants contribute to tumor development or progression as evidenced by their behavior in the experimental model.

Gene→Variant (gene-first): 2064:G776insYVMA 2064:V777L

Genes: 2064

Variants: G776insYVMA 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

[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 8

Evidence Type(s): Oncogenic

Justification: Oncogenic: The mention of "Lung metastases in HER2V777L transgenic mice" suggests that the V777L variant contributes to tumor development or progression in a model organism, indicating its oncogenic potential.

Gene→Variant (gene-first): 2064:V777L

Genes: 2064

Variants: V777L

[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 7

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the combination of HP mutations, including HER2V777L, promotes cancer cell invasion and migration, indicating a role in tumor development or progression. Functional: The passage describes the effects of the HER2V777L variant on cellular migration and invasion, suggesting that it alters molecular or biochemical functions related to these processes.

Gene→Variant (gene-first): 2064:V777L

Genes: 2064

Variants: V777L

[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 6

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 2064:V777L

Genes: 2064

Variants: V777L

[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage describes the PIK3CA H1047R variant as a gain-of-function allele and activating mutation commonly found in human breast cancers, indicating its role in tumor development or progression.

Gene→Variant (gene-first): 5290:H1047R 2064:V777L

Genes: 5290 2064

Variants: H1047R V777L

[Paragraph-level] PMCID: PMC10527017 Section: RESULTS PassageIndex: 2

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage indicates that the HER2V777L variant is involved in tumor formation in mice, suggesting it contributes to tumor development or progression.

Gene→Variant (gene-first): 2064:V777L

Genes: 2064

Variants: V777L

[Paragraph-level] PMCID: PMC5792548 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Diagnostic, Oncogenic

Justification: Predictive: The passage discusses the EGFR T790M mutation in the context of treatment response to osimeritinib and the development of resistance, indicating a correlation with therapy outcomes. Diagnostic: The passage states that the EGFR T790M mutation is used to identify patients with non-small cell lung cancer who are eligible for treatment with osimeritinib, thus classifying it as a diagnostic marker. Oncogenic: The EGFR T790M mutation is described as contributing to resistance in lung cancer, which implies its role in tumor progression and development.

Gene→Variant (gene-first): 1956:T790M

Genes: 1956

Variants: T790M

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

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage indicates that treatment with TK inhibitors has a positive effect on the phenotype induced by the EPHB4-V871I variant, suggesting a correlation with response to therapy. Oncogenic: The mention of the EPHB4-V871I variant inducing a phenotype in neuroblastoma (NB) cell lines implies that it contributes to tumor development or progression.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the EPHB4-V871I variant alters the expression levels of downstream target genes and affects the phosphorylation status of the ERK1-2 pathway, indicating a change in molecular function.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

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

Evidence Type(s): Functional

Justification: Functional: The variant V871I alters molecular function by increasing the expression of target genes and enhancing the phosphorylation of the ERK1-2 pathway.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The variant EPHB4-V871I is associated with increased anchorage-independent growth, indicating its contribution to tumor development or progression as demonstrated by the colony formation assay. Functional: The passage describes the effect of the EPHB4-V871I variant on cellular behavior, specifically its impact on colony formation, which suggests an alteration in molecular or biochemical function.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the EPHB4-V871I variant alters the migration properties of cells, indicating a change in molecular function related to cell behavior.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the EPHB4-V871I variant alters the migration properties of cells, indicating a change in molecular function related to cell behavior.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the EPHB4-V871I variant alters the proliferation rate of cells, indicating a change in molecular or biochemical function. Oncogenic: The increased proliferation rate associated with the EPHB4-V871I variant suggests its contribution to tumor development or progression, as it is linked to cellular behaviors relevant to cancer.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

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

Evidence Type(s): Functional

Justification: Functional: The passage indicates that EPHB4-V871I alters the proliferation and migration of neuroblastoma (NB) cell lines, suggesting a change in molecular or biochemical function.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses the functional characterization of the EPHB4-V871I variant, specifically evaluating its expression and confirming that the mutation does not impair EPHB4 expression at the mRNA and protein level.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 5

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 238:F1174L 2260:N457K 238:R1275Q

Genes: 238 2260

Variants: F1174L N457K R1275Q

[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses mutations in EPHB4 and EphB6 genes, indicating that the variant V871I is associated with a high pathogenic score, suggesting its contribution to tumor development or progression. Functional: The mention of the variant V871I being located in the kinase domain of EPHB4 implies a potential alteration in molecular or biochemical function related to its role in the axon guidance pathway.

Gene→Variant (gene-first): 4613:A417S 2050:V871I

Genes: 4613 2050

Variants: A417S V871I

[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage indicates that the variant F1174L is a somatic mutation found in the ALK gene, which is associated with neuroblastoma (NB), suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): 238:F1174L

Genes: 238

Variants: F1174L

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

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 2050:V871I

Genes: 2050

Variants: V871I

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the introduction of the R164Q mutation led to changes in gene expression and pathway activation, indicating that the variant alters molecular function. Oncogenic: The mention of the A146T, K117N, G13D, and Q61H mutations clustering together and influencing gene expression suggests that these somatic variants contribute to tumor development or progression.

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

Genes: 3845

Variants: A146T G13D K117N L19F Q61H R164Q

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses transcription-profiling experiments and Ras GTPase assay data, indicating that the variants alter molecular or biochemical function, particularly in relation to their clustering and phenotypic characteristics. Oncogenic: The mention of the variants being associated with distinct phenotypes and their clustering suggests that these somatic mutations contribute to tumor development or progression.

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

Genes: 3845

Variants: A146T G12C G12D G12V G13D K117N L19F R164Q

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how specific K-Ras mutations (G12V, L19F, K117N, A146T) are in the active GTP-bound conformation, indicating that these variants alter the molecular function of the K-Ras protein. Oncogenic: The mention of K-Ras mutations being in the active GTP-bound conformation suggests that these somatic variants contribute to tumor development or progression, as they are associated with active signaling pathways in cancer.

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

Genes: 3845

Variants: A146T G12V K117N L19F R164Q

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the transformation potential of various K-Ras mutations, indicating that these mutations contribute to tumor development as evidenced by the formation of foci in NIH3T3 cells after transfection. Functional: The study evaluates the molecular function of K-Ras mutations by assessing their ability to transform cells, which involves alterations in biochemical activity as demonstrated through focus formation assays.

Gene→Variant (gene-first): 3845:A146T 3845:G12D 3845:G12V 3845:G13D 3845:K117N 3845:L19F 3845:Q61H 3845:R164Q

Genes: 3845

Variants: A146T G12D G12V G13D K117N L19F Q61H R164Q

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 4

Evidence Type(s): Diagnostic, Oncogenic, Functional

Justification: Diagnostic: The passage discusses the identification and relative frequencies of K-Ras mutations in human colorectal tumors, indicating their association with the disease. Oncogenic: The mention of K-Ras mutations, including the V600E mutation, suggests their contribution to tumor development or progression, as they are associated with increased mutation frequency in the Ras pathway. Functional: The passage notes the predicted localization of each mutation in the functional domains of the K-Ras protein, indicating an alteration in molecular function.

Gene→Variant (gene-first): 3845:A to C 3845:Ala to Thr 3845:Arg to Gln 3845:C to T 3845:G to A 3845:Lys to Asn 673:V600E 3845:aspartic acid residue at codon 173

Genes: 3845 673

Variants: A to C Ala to Thr Arg to Gln C to T G to A Lys to Asn V600E aspartic acid residue at codon 173

[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 3

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the detection of specific mutations in colorectal tumors, indicating their association with the disease, which supports their use in defining or classifying the disease. Oncogenic: The mention of mutations at codon 19 (G57T, Leu19Phe) and in B-Raf (V600E) suggests that these somatic variants may contribute to tumor development, as they are found in tumor samples.

Gene→Variant (gene-first): 673:G57T 3845:Leu19Phe 673:V600E

Genes: 673 3845

Variants: G57T Leu19Phe V600E

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

Evidence Type(s): Predictive, Prognostic

Justification: Predictive: The passage discusses the response to therapy involving SRA737 and PARP inhibitors (PARPi), indicating a correlation with treatment response in specific PDX models. Prognostic: The mention of a trending increase in survival with combination therapy compared to monotherapy suggests a correlation with disease outcome, although it did not reach statistical significance.

Gene→Variant (gene-first): 142:S4D

Genes: 142

Variants: S4D

[Paragraph-level] PMCID: PMC11253285 Section: RESULTS PassageIndex: 15

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the mechanism by which SRA737 and PARPi synergistically inhibit tumor cell growth, indicating that the variant S3C is involved in tumor development or progression through its effects on cell lines with specific mutations. Functional: The passage describes how exposure to SRA737 results in specific phosphorylation changes in CHK1 and other proteins, indicating that the variant alters molecular or biochemical function related to tumor cell growth.

Gene→Variant (gene-first): 1111:S3C

Genes: 1111

Variants: S3C

This concept has helped me a lot mentally as a student and as someone who will become a teacher. It is super helpful and important to have a term to connect with the feelings of cognitive overload rather than just being unable to explain how you feel overwhelmed.

[Paragraph-level] PMCID: PMC9441062 Section: RESULTS PassageIndex: 15

Evidence Type(s): Diagnostic, Prognostic

Justification: Diagnostic: The passage mentions that patients with L858R mutations were included in a refined cohort, indicating that this variant is used to classify or define a specific group of patients with EGFR mutations in NSCLC. Prognostic: The passage discusses the progression-free survival (PFS) of patients with specific mutations, including L858R, suggesting that this variant correlates with disease outcome independent of therapy.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC9441062 Section: RESULTS PassageIndex: 14

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how the variants T790M, C797S/G, and L718V/Q are associated with resistance mechanisms to EGFR-TKIs, indicating their role in treatment response. Oncogenic: The variants mentioned are described as second-site mutations that contribute to resistance in the context of tumor development and progression in NSCLC.

Gene→Variant (gene-first): 1956:C797S/G 1956:L718V/Q 1956:T790M

Genes: 1956

Variants: C797S/G L718V/Q T790M

[Paragraph-level] PMCID: PMC9441062 Section: RESULTS PassageIndex: 4

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage states that all 71 patients harbored baseline EGFR mutations, including specific variants, indicating their role in defining the patient cohort and confirming the presence of a disease subtype (NSCLC). Oncogenic: The mention of EGFR mutations, including G719C, L858R, and S768I, suggests that these somatic variants contribute to tumor development or progression in the context of non-small cell lung cancer (NSCLC).

Gene→Variant (gene-first): 1956:G719C 1956:L858R 1956:S768I

Genes: 1956

Variants: G719C L858R S768I

[Paragraph-level] PMCID: PMC5355930 Section: ABSTRACT PassageIndex: 6

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the correlation between PIK3CA mutations (H1047R, E545K, E542K) and the response to the therapy everolimus, indicating that these variants are associated with treatment outcomes. Oncogenic: The mention of PIK3CA mutations in the context of tumor analysis suggests that these somatic variants contribute to tumor development or progression, particularly in relation to their response to therapy.

Gene→Variant (gene-first): 5290:E542K 5290:E545K 5290:H1047R

Genes: 5290

Variants: E542K E545K H1047R

[Paragraph-level] PMCID: PMC5355930 Section: ABSTRACT PassageIndex: 4

Evidence Type(s): Diagnostic, Prognostic

Justification: Diagnostic: The passage discusses the analysis of PIK3CA mutations to define patient subgroups, indicating that these variants are used to classify or associate with a disease or subtype. Prognostic: The mention of estimating median progression-free survival (PFS) for patient subgroups defined by PIK3CA mutations suggests a correlation with disease outcome independent of therapy.

Gene→Variant (gene-first): 5290:E542K 5290:E545K 5290:H1047R

Genes: 5290

Variants: E542K E545K H1047R

[Paragraph-level] PMCID: PMC10618648 Section: RESULTS PassageIndex: 20

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The T733I mutation is associated with resistance to lapatinib and sensitivity to adavosertib, indicating its role in predicting treatment response. Oncogenic: The T733I mutation is described as weakly transforming, suggesting it contributes to tumor development or progression in the context of the PDX model.

Gene→Variant (gene-first): 2064:T733I

Genes: 2064

Variants: T733I

[Paragraph-level] PMCID: PMC10618648 Section: RESULTS PassageIndex: 16

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage indicates that ERBB2 mutations (V777L, G778A) were identified in the tyrosine kinase domain, suggesting that these somatic variants contribute to tumor development or progression. Functional: The mention of ERBB2 mutations in the tyrosine kinase domain implies that these variants may alter molecular or biochemical function, which is characteristic of functional evidence.

Gene→Variant (gene-first): 2064:G778A 2064:V777L

Genes: 2064

Variants: G778A V777L

[Paragraph-level] PMCID: PMC10618648 Section: RESULTS PassageIndex: 11

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 2064:E in 72

Genes: 2064

Variants: E in 72

[Paragraph-level] PMCID: PMC3727232 Section: RESULTS PassageIndex: 11

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the detection of BRAF:p.V600E mutations in various tumor types, indicating its association with specific tumor classifications, which supports its use as a biomarker for diagnosis. Oncogenic: The H3F3A:p.K27M mutation is described as being present in specific tumor types, indicating its contribution to tumor development or progression.

Gene→Variant (gene-first): 3021:p.K27M 673:p.V600E

Genes: 3021 673

Variants: p.K27M p.V600E

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

Evidence Type(s): None

Justification: Not enough information in this passage.

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

Genes: 1106 1029 3417 23152

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

[Paragraph-level] PMCID: PMC3727232 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic, Diagnostic

Justification: Oncogenic: The passage discusses the H3F3A:p.K27M mutation and BRAF:p.V600E mutation as recurrent abnormalities in specific tumor types, indicating their contribution to tumor development or progression. Diagnostic: The mention of BRAF:p.V600E mutations being frequent in pleomorphic xanthoastrocytomas suggests its use in defining or classifying this subtype of tumor.

Gene→Variant (gene-first): 3021:p.K27M 673:p.V600E

Genes: 3021 673

Variants: p.K27M p.V600E

[Paragraph-level] PMCID: PMC6938308 Section: ABSTRACT PassageIndex: 6

Evidence Type(s): Oncogenic, Diagnostic

Justification: Oncogenic: The passage discusses somatic mutations in KRAS and BRAF, indicating that these variants contribute to tumor development as they are detected in specimens from patients with AVM. Diagnostic: The presence of specific mutations (G12D, G12V, V600E, Q636X) is used to classify and confirm the mutation status of patients, which is relevant for understanding their disease.

Gene→Variant (gene-first): 3845:G12D 3845:G12V 673:Q636X 673:V600E

Genes: 3845 673

Variants: G12D G12V Q636X V600E

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variant p.Ala636Pro scored as deleterious in an assay, indicating that it alters molecular or biochemical function. Oncogenic: The context of the passage suggests that the variant is associated with bi-allelic MMR loss, which contributes to tumor development in pediatric-onset cancer syndromes, indicating its role in oncogenesis.

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

Genes: 4436

Variants: p.Ala636Pro

[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 7

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the selection of MSH2 mutant cells, specifically the p.Ala636Pro variant, in the context of MMR deficiency, indicating that this somatic variant contributes to tumor development or progression. Functional: The passage describes the behavior of the p.Ala636Pro variant in a selective environment, suggesting that it alters the molecular function of the MSH2 protein, as evidenced by the enrichment of these cells under selective conditions.

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

Genes: 4436

Variants: p.Ala636Pro

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the p.Ala636Pro variant affects the sensitivity to 6-thioguanine, indicating that it alters the molecular function of MSH2 in the context of mismatch repair. Oncogenic: The passage implies that the p.Ala636Pro variant is pathogenic and contributes to the resistance of cells to 6-thioguanine, suggesting a role in tumor development or progression.

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

Genes: 4436

Variants: p.Ala636Pro

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the p.Ala636Pro variant affects the expression levels of MSH2 protein, indicating that it alters molecular function by being barely detectable compared to wild-type MSH2, which demonstrates its destabilizing effect. Oncogenic: The passage describes the use of the p.Ala636Pro variant in a model to disrupt mismatch repair (MMR), suggesting that this somatic variant contributes to tumor development or progression by affecting MSH2 function.

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

Genes: 4436

Variants: p.Ala636Pro

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

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses mutations in specific genes that are associated with druggable tyrosine kinase domains, indicating their relevance in defining or classifying disease subtypes. Oncogenic: The mention of mutations in tyrosine kinase domains suggests that these variants may contribute to tumor development or progression, particularly in the context of cancer-related mutations.

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

Genes: 780 207 405 3084 2048 5156 208 3169 2064

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

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage indicates that the M294K mutation in GATA3 is one of several mutations that include truncation events, suggesting a role in functional inactivation of the protein. Oncogenic: The mention of M294K as a recurrent mutation in tumors suggests that it may contribute to tumor development or progression, particularly in the context of GATA3 being identified as a tumor suppressor.

Gene→Variant (gene-first): 2625:M294K

Genes: 2625

Variants: M294K

[Paragraph-level] PMCID: PMC3383766 Section: RESULTS PassageIndex: 8

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage mentions that AGTR2 harbored two missense mutations (V184I and R251H) and describes AGTR2 as a gene associated with familial hypercholesterolemia, indicating its role in defining or classifying a disease. Oncogenic: The passage discusses mutations in AGTR2 and their potential involvement in angiotensin signaling and tissue fibrosis, which are relevant to tumor development or progression, suggesting a role in oncogenesis.

Gene→Variant (gene-first): 186:R251H 186:V184I

Genes: 186

Variants: R251H V184I

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses mutations in RUNX1, which is implicated in the M2 subtype of AML, indicating that these somatic variants contribute to tumor development or progression. Functional: The passage mentions that mutations in RUNX1 affect its role as a transcription factor, which suggests that these variants alter molecular or biochemical function.

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

Genes: 9757 23451 4216 861 1588 51742

Variants: G168E K666Q K700E N104S R166Q R169K S184L

[Paragraph-level] PMCID: PMC7226056 Section: RESULTS PassageIndex: 7

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 7015:tryptophan-aspartic acid 40

Genes: 7015

Variants: tryptophan-aspartic acid 40

[Paragraph-level] PMCID: PMC7226056 Section: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Oncogenic, Prognostic

Justification: Diagnostic: The passage discusses the reclassification of glioma patients into different types based on expression levels and molecular alterations, indicating that these variants are used to define or classify the disease. Oncogenic: The mention of TERT mutation in gliomas suggests that this somatic variant may contribute to tumor development or progression, as it is associated with different expression levels in tumor types. Prognostic: The passage notes that molecular alterations in gliomas are linked to clinical phenotypes and can predict outcomes, such as overall survival, indicating a prognostic relationship.

Gene→Variant (gene-first): 7015:CGGA 94) in the TCGA

Genes: 7015

Variants: CGGA 94) in the TCGA

[Paragraph-level] PMCID: PMC7499606 Section: RESULTS PassageIndex: 18

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The TP53 Y220C missense mutation is described as a "deleterious somatic mutation," indicating its contribution to tumor development or progression. Predictive: The passage discusses the patient's response to various therapies, including PARP inhibitors and the M6620-carboplatin combination therapy, suggesting that the Y220C variant may correlate with treatment response.

Gene→Variant (gene-first): 7157:Y220C

Genes: 7157

Variants: Y220C

[Paragraph-level] PMCID: PMC2736831 Section: RESULTS PassageIndex: 10

Evidence Type(s): Predictive, Prognostic, Oncogenic

Justification: Predictive: The passage indicates that none of the patients with the BRAF V600E mutation responded to the treatment, suggesting a correlation between the variant and resistance to therapy. Prognostic: The passage reports that BRAF mutation is associated with significantly shorter overall survival (OS) and a trend towards shorter progression-free survival (PFS), indicating its impact on disease outcome independent of therapy. Oncogenic: The BRAF V600E mutation is described as a somatic variant that is part of the study population's tumor mutations, contributing to tumor development or progression.

Gene→Variant (gene-first): 673:V600E

Genes: 673

Variants: V600E

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses heterozygous somatic mutations, including ERBB2 p.L755S, APC p.Q1429fs, and BRAF p.N518S, which are associated with tumor development and progression, indicating their oncogenic potential. Functional: The passage mentions that the biological effect of the detected mutations was predicted using algorithms, suggesting an alteration in molecular or biochemical function related to these variants.

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

Genes: 2064 673 324

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

[Paragraph-level] PMCID: PMC5002925 Section: RESULTS PassageIndex: 3

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the treatment response to therapies such as trastuzumab and FOLFIRI, which are influenced by the presence of specific somatic mutations, indicating a correlation between the variants and treatment response. Oncogenic: The passage identifies somatic mutations in the tumors that are associated with tumor development and progression, particularly noting the likely activating mutation in the ERBB2 p.L755S variant.

Gene→Variant (gene-first): 673:c.1742A>G 2064:c.2264T>C 324:c.4285delC 673:p.Asn581Ser 324:p.Gln1429fs 2064:p.L755S 2064:p.Leu755Ser 673:p.N581S 324:p.Q1429fs

Genes: 673 2064 324

Variants: c.1742A>G c.2264T>C c.4285delC p.Asn581Ser p.Gln1429fs p.L755S p.Leu755Ser p.N581S p.Q1429fs

[Paragraph-level] PMCID: PMC7362646 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses the IDH1 p.R132H mutation as part of the genetic aberrations detected in gliomas, indicating its contribution to tumor development or progression in the context of high-grade gliomas.

Gene→Variant (gene-first): 3417:p.R132H

Genes: 3417

Variants: p.R132H

[Paragraph-level] PMCID: PMC10283448 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the high prevalence of the crizotinib-resistant ROS1-G2032R mutation and its implications for treatment response, indicating a correlation with resistance to therapy. Oncogenic: The mention of the ROS1-G2032R mutation in the context of crizotinib resistance suggests that it contributes to tumor progression, which aligns with the definition of an oncogenic variant.

Gene→Variant (gene-first): 6098:G2032R

Genes: 6098

Variants: G2032R

[Paragraph-level] PMCID: PMC7342819 Section: RESULTS PassageIndex: 2

Evidence Type(s): Diagnostic, Predisposing, Oncogenic

Justification: Diagnostic: The passage discusses the identification of the KRAS p.G12V mutation and the PALB2 mutations in the context of a primary lesion, indicating their association with the disease. Predisposing: The PALB2 c.3114-1G>A mutation is explicitly described as a germline mutation detected in peripheral blood cells, suggesting it confers inherited risk for developing disease. Oncogenic: The PALB2 c.2514+1G>C mutation is described as a somatic mutation, which is associated with tumor development in the context of the primary lesion.

Gene→Variant (gene-first): 79728:c.2514+1G>C 79728:c.3114-1G>A 3845:p.G12V

Genes: 79728 3845

Variants: c.2514+1G>C c.3114-1G>A p.G12V

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

Evidence Type(s): Functional, Prognostic

Justification: Functional: The passage discusses how the alleles of rs16879870 and rs854936 are associated with increased mRNA expression levels of their corresponding genes, indicating an alteration in molecular function. Prognostic: The passage reports that higher expression levels of the genes GJB7 and RTN4R correlate with worse prognosis in HNSCC patients, indicating a relationship with disease outcome independent of therapy.

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

Genes: NA

Variants: rs16879870 rs854936

[Paragraph-level] PMCID: PMC7099049 Section: RESULTS PassageIndex: 11

Evidence Type(s): Prognostic

Justification: Prognostic: The passage discusses the effects of risk genotypes, including rs2761591, on death with HNSCC, indicating a correlation with disease outcome.

Gene→Variant (gene-first): 341019:rs2761591

Genes: 341019

Variants: rs2761591

[Paragraph-level] PMCID: PMC7099049 Section: RESULTS PassageIndex: 9

Evidence Type(s): Prognostic, Predictive

Justification: Prognostic: The passage discusses the ability of a model to predict survival in HNSCC, indicating a correlation between the variant and disease outcome. Predictive: The mention of using NRG in a prediction model for HNSCC survival suggests a relationship with treatment response or sensitivity, aligning with predictive evidence.

Gene→Variant (gene-first): 2264:AUC from 0

Genes: 2264

Variants: AUC from 0

[Paragraph-level] PMCID: PMC7099049 Section: RESULTS PassageIndex: 7

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The passage discusses how the number of risk genotypes (NRG) correlates with the hazard of death in patients with HNSCC, indicating a relationship between the variants and disease outcome. Diagnostic: The variants are used to define and classify patients into groups based on the number of risk genotypes, which is associated with survival outcomes in HNSCC.

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

Genes: NA 388325 341019

Variants: rs16879870 rs2641256 rs2761591 rs854936

[Paragraph-level] PMCID: PMC7099049 Section: RESULTS PassageIndex: 6

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The passage discusses the association of specific SNP genotypes with survival outcomes in HNSCC, indicating that these variants correlate with risk of death independent of therapy. Diagnostic: The passage mentions the classification performance of risk genotypes of selected SNPs, suggesting their use in defining or classifying disease risk.

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

Genes: NA 388325 341019

Variants: rs16879870 rs2641256 rs2761591 rs854936

[Paragraph-level] PMCID: PMC7099049 Section: RESULTS PassageIndex: 5

Evidence Type(s): Prognostic

Justification: Prognostic: The passage discusses the correlation of specific SNPs with HNSCC patients' survival, indicating that these variants are associated with disease outcome independent of therapy.

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

Genes: NA 388325 341019

Variants: rs16879870 rs2641256 rs2761591 rs854936

[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 17

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the association of the R108K variant with clinical responses to EGFR kinase inhibitors, indicating a correlation with treatment response. Oncogenic: The R108K variant is identified in gliomas, suggesting its potential role in tumor development or progression, particularly in the context of EGFR amplification.

Gene→Variant (gene-first): 1956:R108K

Genes: 1956

Variants: R108K

[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 16

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how the presence of EGFR missense mutants, including L858R and L861Q, may sensitize transformed cells to EGFR kinase inhibitors, indicating a correlation with treatment response. Oncogenic: The identical missense mutations are described as having oncogenicity and playing a role in gliomagenesis, suggesting that these somatic variants contribute to tumor development.

Gene→Variant (gene-first): 1956:L858R 1956:L861Q 1956:T790M

Genes: 1956

Variants: L858R L861Q T790M

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the EGFR mutants (R108K, T263P, A289V, G598V, L861Q) alter the molecular function of the EGF-signaling pathway, specifically showing increased tyrosine phosphorylation and differences in receptor downregulation in response to EGF stimulation.

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

Genes: 1956

Variants: A289V G598V L861Q R108K T263P

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

Evidence Type(s): Functional

Justification: Functional: The examination of other EGFR missense mutants (T263P, G598V, L861Q) also shows an increase in phosphotyrosine content, suggesting that these variants similarly affect the molecular function of the receptor.

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

Genes: 1956

Variants: A289V G598V L861Q T263P

[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage describes how NIH-3T3 cells expressing the EGFR missense mutants (R108K, T263P, A289V, G598V, and L861Q) produced large tumors in mice, indicating that these variants contribute to tumor development.

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

Genes: 1956

Variants: A289V G598V L861Q R108K T263P

[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses the oncogenicity of EGFR missense mutations, indicating that the expression of these variants (R108K, T263P, A289V, G598V, and L861Q) in NIH-3T3 cells leads to anchorage-independent colony formation, a hallmark of tumorigenic behavior.

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

Genes: 1956

Variants: A289V G598V L861Q R108K T263P

[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the prevalence of specific EGFR missense mutations (R108K, T263P, A289V, and G598V) in gliomas, indicating their association with the disease and their representation in the receptor pool, which supports their use in defining or classifying the disease. Oncogenic: The mention of EGFR missense mutations in the context of gliomas suggests that these somatic variants contribute to tumor development or progression, as they are associated with the receptor pool in tumor samples.

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

Genes: 1956

Variants: A289V G598V R108K T263P

[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 4

Evidence Type(s): Diagnostic, Oncogenic, Predisposing

Justification: Diagnostic: The passage discusses the identification of EGFR missense mutations in glioblastomas and their association with the disease, indicating that these mutations can be used to classify or define the tumor type. Oncogenic: The passage mentions that the identified EGFR mutations contribute to tumor development in glioblastomas, particularly noting the presence of somatic mutations in the tumor samples. Predisposing: The passage specifies that one of the mutations (E330K) was identified as germline, indicating it confers inherited risk for developing disease.

Gene→Variant (gene-first): 1956:A289 1956:A289D 1956:A289T 1956:E330K 1956:L861Q 1956:R108 1956:R324L

Genes: 1956

Variants: A289 A289D A289T E330K L861Q R108 R324L

[Paragraph-level] PMCID: PMC4385014 Section: ABSTRACT PassageIndex: 4

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the sensitivity of NSCLC cell lines with specific EGFR mutations (L858R and T790M) to the anti-proliferative effect of erlotinib, indicating a correlation with treatment response. Oncogenic: The presence of the L858R and T790M mutations in the cell lines suggests that these somatic variants contribute to tumor development or progression, as they are associated with specific cancer cell lines.

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

Genes: 1956

Variants: L858R T790M

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 19

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the presence of specific PIK3CA mutations in patients with distinct clinical features, indicating that these mutations are associated with certain syndromes, such as linear nevus sebaceous or Schimmelpenning syndrome and CLOVES syndrome. Oncogenic: The passage mentions that the PIK3CA mutations are "hotspot" mutations commonly seen in cancer, suggesting that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 5290:p.Glu542Lys 5290:p.Glu545Lys 5290:p.His1047Arg

Genes: 5290

Variants: p.Glu542Lys p.Glu545Lys p.His1047Arg

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 17

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the presence of the p.Glu453Lys and p.Gly914Arg mutations in patients with specific congenital conditions, indicating their association with the phenotypes observed, which supports their use in defining or classifying the disease. Oncogenic: The p.Glu453Lys and p.Gly914Arg mutations are described in the context of patients with congenital overgrowth syndromes, suggesting a role in tumor development or progression, particularly in the context of somatic mutations.

Gene→Variant (gene-first): 5290:p.Glu453Lys 5290:p.Gly914Arg

Genes: 5290

Variants: p.Glu453Lys p.Gly914Arg

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 16

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the presence of specific mutations (p.Arg93Gln, p.Gly106Val, p.Cys378Tyr) in patients with phenotypes that overlap with or suggest variants of MCAP, indicating that these mutations are associated with defining or classifying the disease. Oncogenic: The passage describes the mutations as somatic variants present in patients with specific phenotypes, suggesting their contribution to tumor development or progression, particularly in the context of the patients' conditions.

Gene→Variant (gene-first): 5290:p.Arg93Gln 5290:p.Cys378Tyr 5290:p.Gly106Val

Genes: 5290

Variants: p.Arg93Gln p.Cys378Tyr p.Gly106Val

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 14

Evidence Type(s): Diagnostic, Predisposing

Justification: Diagnostic: The passage discusses individuals with mosaic PIK3CA mutations, including the p.Glu726Lys variant, in the context of classic features of MCAP, indicating its role in defining or classifying the disease. Predisposing: The passage mentions that several patients with the p.Glu726Lys mutation had various clinical findings associated with MCAP, suggesting an inherited risk for developing this condition.

Gene→Variant (gene-first): 5290:p.Glu726Lys

Genes: 5290

Variants: p.Glu726Lys

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

Evidence Type(s): Oncogenic, Diagnostic

Justification: Oncogenic: The passage discusses mutations that are proven or predicted to have a gain-of-function mechanism, indicating that these somatic variants contribute to tumor development or progression. Diagnostic: The mention of Glu545Ala and Glu545Lys mutations being detected in individuals with undefined "Cowden-like" features suggests an association with a specific disease or phenotype, supporting their use in diagnosis.

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

Genes: 5290 7249

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

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 9

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the association of PIK3CA mutations with developmental pediatric disorders, indicating that these mutations are used to classify or define the disease phenotypes. Oncogenic: The mention of PIK3CA mutations, particularly the hotspot mutations, suggests their role in tumor development or progression, as they are frequently observed in affected individuals.

Gene→Variant (gene-first): 5290:p.Glu542Lys 5290:p.Glu545Lys 5290:p.Glu726Lys 5290:p.Gly914Arg 5290:p.His1047Arg

Genes: 5290

Variants: p.Glu542Lys p.Glu545Lys p.Glu726Lys p.Gly914Arg p.His1047Arg

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 8

Evidence Type(s): Diagnostic

Justification: Diagnostic: The passage discusses the identification of mutations in patients, including the p.Arg93Gln variant, suggesting its association with specific cases and indicating its role in defining or confirming a disease.

Gene→Variant (gene-first): 5290:p.Arg93Gln

Genes: 5290

Variants: p.Arg93Gln

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses mutations of PIK3CA, including p.Glu545Lys and p.His1047Arg, which are identified as oncogenic mutations contributing to tumor development or progression, as indicated by their presence in the Catalogue of Somatic Mutations in Cancer (COSMIC). Functional: The passage mentions the alternative allele percentages (AAP) of the mutations, indicating that these variants may alter molecular or biochemical function, as evidenced by the variation in AAPs across different sample types.

Gene→Variant (gene-first): 5290:p.Glu545Lys 5290:p.His1047Arg

Genes: 5290

Variants: p.Glu545Lys p.His1047Arg

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 11

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of the tumor to the treatment with CHMFL-KIT-031, indicating a correlation between the V559D variant and the sensitivity to this specific therapy, as evidenced by tumor growth inhibition. Oncogenic: The V559D variant is implicated in tumor progression, as the passage describes its role in a mouse model where the variant is present and the tumor's response to treatment is evaluated.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The variant V559D is discussed in the context of tumor growth inhibition, indicating that it contributes to tumor development or progression in the specified cell model. Predictive: The mention of CHMFL-KIT-031 inhibiting tumor growth suggests a correlation between the V559D variant and response to this specific therapy.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

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

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the inhibitory effect of CHMFL-KIT-031 against the KIT V559D mutant, indicating a correlation with response to therapy, as evidenced by the IC50 values and selectivity over the wild-type KIT. Functional: The variant KIT V559D is shown to alter the molecular function by affecting the phosphorylation of specific sites and downstream mediators, demonstrating its role in biochemical activity as tested in various assays.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 8

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage indicates that CHMFL-KIT-031 selectively inhibits the KIT V559D mutant, suggesting a correlation with response to therapy. Oncogenic: The mention of the KIT V559D mutant in the context of selective inhibition implies that this somatic variant contributes to tumor development or progression.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

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

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the binding and selectivity of CHMFL-KIT-031 to the V559D, L576P, and A829P variants, indicating their potential response to therapy, particularly in the context of inhibitor selectivity. Functional: The results indicate that the variants (V559D, L576P, A829P) alter the binding characteristics of the compound CHMFL-KIT-031, suggesting a change in molecular function related to kinase activity.

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

Genes: 3815

Variants: A829P L576P V559D

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the KIT V559D mutant affects phosphorylation at specific sites, indicating that the variant alters molecular function related to protein activity. Oncogenic: The context of the passage suggests that the KIT V559D variant contributes to tumor development or progression, as it is involved in the anti-proliferation assay of transformed cells.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

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

Evidence Type(s): Functional

Justification: Functional: The passage indicates that the variant V559D alters the molecular function of the KIT protein by affecting its auto-phosphorylation activity in specific cells.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 3

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of various KIT variants, including V559D, L576P, and others, to different therapies such as CHMFL-KIT-031 and Imatinib, indicating their correlation with treatment sensitivity and resistance. Oncogenic: The variants mentioned, particularly V559D and L576P, are described in the context of their role in transforming BaF3 cells, suggesting that they contribute to tumor development or progression.

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

Genes: 3815

Variants: D816V L576P N822K T670I V559D V654A

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

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage indicates that CHMFL-KIT-031 selectively inhibits the proliferation of cells with the V559D variant, suggesting a correlation with response to this specific therapy. Oncogenic: The mention of the V559D variant in the context of inhibiting cell proliferation implies that it contributes to tumor development or progression, as it is associated with a specific cell line used in cancer research.

Gene→Variant (gene-first): 3815:V559D

Genes: 3815

Variants: V559D

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

Evidence Type(s): Oncogenic, Diagnostic

Justification: Oncogenic: The passage discusses the presence of the p.M90I mutation in lung adenocarcinoma cell lines and its association with human primary lung adenocarcinomas, indicating that this somatic variant contributes to tumor development or progression. Diagnostic: The p.M90I mutation is mentioned as being seen in human primary lung adenocarcinomas, suggesting its role in defining or classifying the disease.

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

Genes: 6016

Variants: p.M90I

[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the RIT1 Q40L mutation contributes to tumor development by activating MEK and ERK pathways, indicating its role in oncogenic signaling. Functional: The variant Q40L alters the molecular function of RIT1, as it induces phosphorylation of MEK and ERK, demonstrating a change in biochemical activity associated with the mutation.

Gene→Variant (gene-first): 6016:Q40L

Genes: 6016

Variants: Q40L

[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 7

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how mutated RIT1 variants, including Q79L, G12V, and L858R, induce cellular transformation and tumor formation, indicating their role in tumor development. Functional: The passage describes the ability of specific RIT1 mutations to induce colony formation in soft agar, suggesting that these variants alter the molecular function of RIT1 in a way that promotes transformation.

Gene→Variant (gene-first): 3845:G12V 1956:L858R 6016:Q40 6016:Q40L 6016:Q79L

Genes: 3845 1956 6016

Variants: G12V L858R Q40 Q40L Q79L

[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 6

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the presence of the RIT1 p.M90I variant in different cancer types, indicating its association with malignancies, which supports its use in defining or classifying disease subtypes. Oncogenic: The mention of somatic RIT1 mutations in myeloid malignancies and their overlap with mutations in lung adenocarcinoma suggests that these variants contribute to tumor development or progression.

Gene→Variant (gene-first): 6016:F82L 6016:M90I 6016:p.M90I

Genes: 6016

Variants: F82L M90I p.M90I

[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage suggests that RIT1 switch II domain mutations, including p.R122L, may function as oncogenes in lung adenocarcinoma, indicating a role in tumor development or progression.

Gene→Variant (gene-first): 6016:p.R122L

Genes: 6016

Variants: p.R122L

[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 4

Evidence Type(s): Diagnostic, Predisposing

Justification: Diagnostic: The passage discusses the recurrent alteration of RIT1 alanine 77 and mentions that one of the mutated samples harbored a p.A77P mutation, indicating its association with tumor classification. Predisposing: The passage suggests that p.A77S may represent a rare germline variant, indicating a potential inherited risk for disease, although it is noted to be unlikely.

Gene→Variant (gene-first): NA:alanine 77 6016:p.A77P 6016:p.A77S

Genes: NA 6016

Variants: alanine 77 p.A77P p.A77S

[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses non-synonymous somatic mutations of RIT1, including the p.M90I variant, in the context of lung adenocarcinomas, indicating that these mutations contribute to tumor development or progression.

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

Genes: 6016

Variants: p.M90I

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

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses a novel loss of function mutation (E384X) in ERRFI1 that is associated with a patient's metastatic tumor, indicating that this somatic variant contributes to tumor development or progression. Functional: The passage mentions nearly complete loss of function of ERRFI1 due to the E384X mutation, suggesting that this variant alters the molecular or biochemical function of the protein.

Gene→Variant (gene-first): 672:E384X

Genes: 672

Variants: E384X

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

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 1767:G C

Genes: 1767

Variants: G C

[Paragraph-level] PMCID: PMC3923676 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The variant E384X in ERRFI1 is described as being overexpressed in a tumor, indicating its potential role in tumor development or progression. Predictive: The passage discusses the therapeutic relevance of FGFR2 fusions and their treatment with FGFR inhibitors, suggesting a correlation with response to therapy.

Gene→Variant (gene-first): 672:E384X

Genes: 672

Variants: E384X

[Paragraph-level] PMCID: PMC7081042 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Diagnostic, Oncogenic

Justification: Predictive: The passage discusses how certain HER2 mutations, such as S310F, S310Y, R678Q, D769H, and I767M, correlate with favorable outcomes and good responses to anti-HER2 therapy, indicating their predictive value for treatment efficacy. Diagnostic: The passage mentions the identification of HER2 SNPs in HER2-positive breast cancer patients and their relationship with clinical outcomes, suggesting that these variants can be used to classify or define the disease subtype. Oncogenic: The passage indicates that somatic mutations in HER2 are linked to resistance to anti-HER2 therapy, suggesting that these mutations contribute to tumor development or progression.

Gene→Variant (gene-first): 2064:D769H 2064:D769Y 2064:I767M 1956:K753I 2064:L755S 2064:R678Q 2064:S310F 2064:S310Y 2064:V842I

Genes: 2064 1956

Variants: D769H D769Y I767M K753I L755S R678Q S310F S310Y V842I

[Paragraph-level] PMCID: PMC4159563 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The K27M-H3 mutation is described as being exclusively found in tumors with specific WHO grade II-IV astrocytoma histology, indicating its role in classifying and defining the disease subtype. Oncogenic: The passage indicates that the K27M-H3 mutation is associated with tumors that behave clinically as high-grade astrocytomas, suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): 90:K27M

Genes: 90

Variants: K27M

[Paragraph-level] PMCID: PMC3366948 Section: RESULTS PassageIndex: 22

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the presence of TYK2 mutations in T-ALL cell lines and suggests that these mutations may not represent an oncogenic event important for leukemia development in vivo, indicating a potential role in tumor progression. Functional: The analysis of the transforming properties of the TYK2 variants in Ba/F3 cells indicates that the variants do not show major differences in function compared to wild type TYK2, suggesting an assessment of molecular function.

Gene→Variant (gene-first): 4486:A35V 5395:C192Y 7297:R1027H

Genes: 4486 5395 7297

Variants: A35V C192Y R1027H

[Paragraph-level] PMCID: PMC3366948 Section: RESULTS PassageIndex: 18

Evidence Type(s): Oncogenic

Justification: Oncogenic: The variant H1297Y is described as a somatic variant confirmed in a patient case, indicating its contribution to tumor development or progression in the context of T-ALL.

Gene→Variant (gene-first): 80312:H1297Y

Genes: 80312

Variants: H1297Y

[Paragraph-level] PMCID: PMC3366948 Section: RESULTS PassageIndex: 15

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage describes that the M511I mutation transformed IL3 dependent 32D cells and induced T-ALL in mice, indicating its role in tumor development. Additionally, the A572V mutation was shown to transform cytokine dependent hematopoietic cells and induce leukemia in mice, further supporting its oncogenic potential. Functional: The passage discusses how specific mutations in JAK3, such as A572T and A572V, alter the function of the protein, as evidenced by their ability to transform cells and induce leukemia, indicating a change in molecular or biochemical function.

Gene→Variant (gene-first): 3718:A572 3718:A572T 3718:A572V 3718:M511I

Genes: 3718

Variants: A572 A572T A572V M511I

[Paragraph-level] PMCID: PMC8078423 Section: ABSTRACT PassageIndex: 8

Evidence Type(s): Predictive, Diagnostic

Justification: Predictive: The passage discusses the improved overall survival (OS), objective response rate (ORR), and progression-free survival associated with the treatment of encorafenib plus cetuximab in patients with BRAF V600E mCRC, indicating a correlation with therapy response. Diagnostic: The mention of BRAF V600E in the context of metastatic colorectal cancer (mCRC) suggests its role in defining or classifying a specific disease subtype, as it is associated with a particular treatment regimen.

Gene→Variant (gene-first): 673:V600E

Genes: 673

Variants: V600E

[Paragraph-level] PMCID: PMC8078423 Section: ABSTRACT PassageIndex: 4

Evidence Type(s): Predictive, Diagnostic

Justification: Predictive: The passage discusses a trial involving patients with BRAF V600E-mutant mCRC and mentions endpoints related to overall survival (OS) and objective response rate (ORR), indicating a correlation with treatment response. Diagnostic: The mention of "BRAF V600E-mutant mCRC" implies that the variant is used to classify or define a specific subtype of cancer, which aligns with diagnostic evidence.

Gene→Variant (gene-first): 673:V600E

Genes: 673

Variants: V600E

[Paragraph-level] PMCID: PMC8078423 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Predictive, Diagnostic

Justification: Predictive: The passage discusses the correlation of the BRAFV600E variant with improved overall survival and objective response rate in patients treated with specific therapies, indicating its predictive value for treatment response. Diagnostic: The mention of BRAFV600E in the context of metastatic colorectal cancer suggests its role in defining or classifying a specific subtype of the disease, supporting its use as a diagnostic marker.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC9365372 Section: RESULTS PassageIndex: 13

Evidence Type(s): Predictive, Diagnostic

Justification: Predictive: The passage discusses the overall response rate (ORR) and disease control rate (DCR) in patients with the T790M variant, indicating a correlation with treatment response to abivertinib. Diagnostic: The mention of T790M+ in the context of evaluating patient cohorts suggests that this variant is used to classify or define a specific group of patients for treatment assessment.

Gene→Variant (gene-first): 1956:T790M

Genes: 1956

Variants: T790M

[Paragraph-level] PMCID: PMC9365372 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive

Justification: Predictive: The passage discusses the response rates of patients with the T790M variant treated with specific doses of abivertinib, indicating a correlation between the variant and treatment response.

Gene→Variant (gene-first): 1956:T790M

Genes: 1956