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

Evidence Type(s): Functional, Oncogenic

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

Gene→Variant (gene-first): 2064:S310F

Genes: 2064

Variants: S310F

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

Evidence Type(s): Functional

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

Gene→Variant (gene-first): 2064:S310F

Genes: 2064

Variants: S310F

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

Evidence Type(s): Functional, Oncogenic

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

Gene→Variant (gene-first): 2064:S310F

Genes: 2064

Variants: S310F

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 2064

Variants: S310 S310F

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

Evidence Type(s): Predictive, Functional

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

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

Genes: 2064

Variants: G309 G309A G309E S309A S310 S310F S310Y

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

Evidence Type(s): Predictive, Functional

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

Gene→Variant (gene-first): 2064:S310F

Genes: 2064

Variants: S310F

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

Evidence Type(s): Predictive, Functional

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

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

Genes: 1956

Variants: V769dupASV

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

Evidence Type(s): Predictive, Functional

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

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

Genes: 2261 2260

Variants: V555M V561M

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

Evidence Type(s): Predictive, Functional

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

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

Genes: 2263 2261

Variants: I538 I538V K650E N540 N540K N540S R669G V555M

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

Evidence Type(s): Predictive, Functional

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

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

Genes: 2263 2261

Variants: I538V K650E N540K N540S R669G V555M

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

Evidence Type(s): Functional

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

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

Genes: 2260

Variants: D641 L630 V561

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 2261 2260

Variants: K650E R669G R675 R675G

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

Evidence Type(s): Functional

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

Gene→Variant (gene-first): 2261:R669G

Genes: 2261

Variants: R669G

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

Evidence Type(s): Functional

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

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

Genes: 2261 2260 2263

Variants: H650 R675 R675G Y653

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 2260 2261

Variants: R to G R669 R675G

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

Evidence Type(s): Functional

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

Gene→Variant (gene-first): 2261:R669G

Genes: 2261

Variants: R669G

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 2261 2263 2260

Variants: D617G E466K G637W R669

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

Evidence Type(s): Functional

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

Gene→Variant (gene-first): 2261:R669G

Genes: 2261

Variants: R669G

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 2261

Variants: G697C K650E N540K

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

Evidence Type(s): Functional, Oncogenic

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

Gene→Variant (gene-first): 2261:K650E

Genes: 2261

Variants: K650E

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 2261 2260

Variants: D617 D617G G to W G637 G637W

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

Evidence Type(s): Functional, Oncogenic

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

Gene→Variant (gene-first): 2261:G697C

Genes: 2261

Variants: G697C

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

Evidence Type(s): Predictive, Functional

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

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

Genes: 2260 2261

Variants: D641G D641N V555 V555M

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 2263 2261

Variants: I538V K650E K650N N540K N540S R669G R669Q

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

Evidence Type(s): Functional

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

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

Genes: 2261

Variants: K650 N540K

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

Evidence Type(s): Oncogenic, Functional

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

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

Genes: 2261

Variants: G697 G697C K650 N540

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

Evidence Type(s): Functional, Diagnostic

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

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

Genes: 2120

Variants: N356fs S105fs V345fs Y103fs

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 2120

Variants: N356fs S105fs V345fs Y103fs

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

Evidence Type(s): Diagnostic, Functional

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

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

Genes: 3091

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

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

Evidence Type(s): Functional

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

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

Genes: 5290

Variants: H1047 H1047L

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 5290

Variants: H1047R

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

Evidence Type(s): Functional

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

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

Genes: 5290 5295

Variants: C420 C420R E545K N345 N564 N564D

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

Evidence Type(s): Functional

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

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

Genes: 5290

Variants: G1049R H1047L H1047R

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

Evidence Type(s): Functional

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

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

Genes: 5290 5295

Variants: C420R E545K N564D

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

Evidence Type(s): Functional

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

Gene→Variant (gene-first): 5290:E545K

Genes: 5290

Variants: E545K

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

Evidence Type(s): Functional

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

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

Genes: 5294

Variants: K942Q R949D

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

Evidence Type(s): Functional, Oncogenic

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

Gene→Variant (gene-first): 5290:D915N

Genes: 5290

Variants: D915N

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

Evidence Type(s): Functional

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

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

Genes: 5290

Variants: deletion of residues 1051-1068

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

Evidence Type(s): Oncogenic, Functional

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

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

Genes: 5290

Variants: H1047R

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

Evidence Type(s): Functional

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

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

Genes: 5294

Variants: K942 R949

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

Evidence Type(s): Predictive, Functional

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

Gene→Variant (gene-first): 2322:D835H

Genes: 2322

Variants: D835H

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 2322

Variants: D835Y/V

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

Evidence Type(s): Functional, Predictive

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

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

Genes: 2322

Variants: D835 D835E/N

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

Evidence Type(s): Predictive, Functional

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

Gene→Variant (gene-first): 2322:D835

Genes: 2322

Variants: D835

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

Evidence Type(s): Functional

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

Gene→Variant (gene-first): 2322:D835

Genes: 2322

Variants: D835

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

Evidence Type(s): Oncogenic, Functional

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

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

Genes: 7157 694

Variants: p.E46K p.Q36H

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

Evidence Type(s): Functional, Predictive

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

Gene→Variant (gene-first): 2064:V777L

Genes: 2064

Variants: V777L

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

Evidence Type(s): Functional, Oncogenic

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

Gene→Variant (gene-first): 2064:V777L

Genes: 2064

Variants: V777L

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

Evidence Type(s): Oncogenic, Functional

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

Gene→Variant (gene-first): 2064:V777L

Genes: 2064

Variants: V777L

[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: 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: 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: 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: 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

[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: 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: 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: 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: 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: 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: ABSTRACT PassageIndex: 3

Evidence Type(s): Prognostic, Functional

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

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

Genes: NA 388325 341019

Variants: rs16879870 rs2641256 rs2761591 rs854936

[Paragraph-level] PMCID: 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: 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: 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: 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: 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: 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: 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: 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: PMC8008494 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the sensitivity of specific BRCA2 variants to PARP inhibitors, indicating a correlation with response to therapy. Functional: The passage describes how the BRCA2 variants influence the ability to restore survival in mouse embryonic stem cells and their functional classification based on drug sensitivity assays.

Gene→Variant (gene-first): 675:c.8723T>G 675:c.8905G>A 675:p.Val2908Gly 675:p.Val2969Met

Genes: 675

Variants: c.8723T>G c.8905G>A p.Val2908Gly p.Val2969Met

[Paragraph-level] PMCID: PMC8008494 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how specific variants alter the function of the protein, indicating that certain amino acid substitutions result in loss of function or maintain functionality, which is characteristic of functional evidence. Oncogenic: The context of the variants being associated with loss of function in a cancer-related gene (BRCA2) suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): NA:2619 from Trp to Gly 675:2723 from Asp to Asn 353:7522G>A 353:7807G>T 353:7874G>A 353:7879A>G NA:Leu3180 353:Phe/Asn 353:c.7522G>C 675:c.7880T>A 675:c.9370A>C 675:c.9371A>T 675:c.9539T>C 675:p.Ala2603Ser 675:p.Arg2625Lys 675:p.Asn3124His 353:p.Gly2508Arg 675:p.Gly2508Ser 675:p.Ile2627Val

Genes: NA 675 353

Variants: 2619 from Trp to Gly 2723 from Asp to Asn 7522G>A 7807G>T 7874G>A 7879A>G Leu3180 Phe/Asn c.7522G>C c.7880T>A c.9370A>C c.9371A>T c.9539T>C p.Ala2603Ser p.Arg2625Lys p.Asn3124His p.Gly2508Arg p.Gly2508Ser p.Ile2627Val

[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: PMC6791388 Section: RESULTS PassageIndex: 14

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses how increased phosphorylation of CREB at Ser133 may promote MEK inhibitor resistance, indicating a correlation with treatment response. Functional: The variant at Ser133 is described in the context of altering the phosphorylation state of CREB, which affects its molecular function and activity.

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

Genes: 7157

Variants: S133 Ser133 Serine 133

[Paragraph-level] PMCID: PMC6547681 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Predictive, Functional

Justification: Predictive: The variant G101V is associated with drug resistance to venetoclax in patients, indicating a correlation with treatment response. Functional: The passage discusses the biochemical analyses of the G101V mutant, revealing how it alters the affinity of venetoclax, which relates to its molecular function.

Gene→Variant (gene-first): 596:G101V

Genes: 596

Variants: G101V

[Paragraph-level] PMCID: PMC6547681 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the emergence of the G101V mutation in patients failing therapy with venetoclax, indicating a correlation between the variant and resistance to this specific therapy. Functional: The passage describes how the G101V mutation alters the binding of venetoclax to BCL-2, indicating a change in molecular function related to drug resistance.

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

Genes: 596

Variants: E152 E152A G101V V101

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 596

Variants: E152 E152A G101V V101

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

Evidence Type(s): Functional, Predictive

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

Gene→Variant (gene-first): 596:G101V

Genes: 596

Variants: G101V

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

Evidence Type(s): Functional, Predictive

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

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

Genes: 596

Variants: E152 E152A G101A G101V

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

Evidence Type(s): Predictive, Functional

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

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

Genes: 596

Variants: F104C F104L G101V

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

Evidence Type(s): Functional

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

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

Genes: 596

Variants: F104 F104L L104

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

Evidence Type(s): Functional, Predictive

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

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

Genes: 596

Variants: E152 G101 G101A G101V

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants E401G and S310F alter molecular function by enhancing C-terminal phosphorylation and maintaining the stability of the EGFR-HER2 heterodimer. Oncogenic: The passage indicates that ERBB2 E401G-transduced cells exhibit increased tumor growth capacity in vivo, suggesting that this variant contributes to tumor development or progression.

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

Genes: 2176 2064

Variants: E401G S310F

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the evaluation of the phosphorylation of human epidermal growth factor receptor 2 and related proteins, as well as the investigation of the biological effects of the ERBB2 E401G variant, indicating an alteration in molecular function. Oncogenic: The mention of S310F and E321G as known activating mutations suggests that these variants contribute to tumor development or progression, aligning with the oncogenic evidence type.

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

Genes: 7157 2176 2064

Variants: E321G E401G S310F

[Paragraph-level] PMCID: PMC8881279 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Functional

Justification: Functional: The passage discusses the aim to clarify the biological functions of the ERBB2 E401G variant, indicating an interest in how this variant alters molecular or biochemical function.

Gene→Variant (gene-first): 4609:1157A > G 2176:E401G

Genes: 4609 2176

Variants: 1157A > G E401G

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 2176 2064

Variants: E401G S310F

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 2176 2064

Variants: E401G S310F

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

Evidence Type(s): Functional

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

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

Genes: 2176 2064

Variants: E401G S310F

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

Evidence Type(s): Functional

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

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

Genes: 2176

Variants: p.(E401G)

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 2176 2064

Variants: E401G S310F

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

Evidence Type(s): Functional

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

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

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

Evidence Type(s): Functional

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

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

Genes: 2176 2064

Variants: E401G S310F

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

Evidence Type(s): Functional

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

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

Genes: 7157 2176 2064

Variants: E321G E401G S310F

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

Evidence Type(s): Functional

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

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

Genes: 2064 7157 2176

Variants: D845A E321G E401G S310F

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

Evidence Type(s): Functional

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

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

Genes: 2176 2064

Variants: E401G S310F

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

Evidence Type(s): Oncogenic, Functional

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

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 16

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the behavior of Kras mutations, specifically KrasC118S and KrasG13D, in the context of transformation and signaling, indicating their role in tumor development and progression. Functional: The analysis of P-Erk1/2 levels upon EGF treatment suggests that the KrasC118S variant alters molecular function related to signaling pathways, as evidenced by the immunoblotting results.

Gene→Variant (gene-first): 4843:C118 4843:C118S 3845:G13D 4893:Q61L

Genes: 4843 3845 4893

Variants: C118 C118S G13D Q61L

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 15

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the identification of oncogenic mutations, specifically Q61R/L, in the context of tumor development in Kras+/C118S mice, indicating that these variants contribute to tumor progression. Functional: The mention of the C118S variant in the context of its allelic origin and mutation status suggests an alteration in molecular function related to the Kras gene, which is relevant to its role in oncogenesis.

Gene→Variant (gene-first): 4843:C118S 4893:Q61R 3845:Q61R/L

Genes: 4843 4893 3845

Variants: C118S Q61R Q61R/L

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 13

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the KrasG12D allele as promoting lung tumorigenesis, indicating its role in tumor development. Functional: The passage describes the C118S mutation's effect on the tumorigenic activity of the oncogenic Kras allele and its interaction with the non-oncogenic allele, suggesting a change in molecular function related to tumor suppression.

Gene→Variant (gene-first): 4843:C118S 3845:G12D

Genes: 4843 3845

Variants: C118S G12D

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the impact of the KrasC118S variant on tumor progression and its association with different tumor types, indicating that this somatic variant contributes to tumor development or progression. Functional: The analysis shows that the KrasC118S variant is associated with reduced P-Akt signaling, suggesting that it alters molecular function related to signaling pathways involved in tumor biology.

Gene→Variant (gene-first): 4843:C118S

Genes: 4843

Variants: C118S

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the KrasC118S variant contributes to tumor development by resulting in fewer tumors and smaller average tumor sizes in mice, indicating its role in tumor progression. Functional: The presence of the KrasC118S allele is shown to alter the tumor characteristics, specifically leading to a shift towards smaller tumors, which suggests an alteration in molecular or biochemical function related to tumor development.

Gene→Variant (gene-first): 4843:C118S

Genes: 4843

Variants: C118S

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the KrasC118S mutation in the context of its role in carcinogenesis and tumor development, particularly in relation to urethane-induced lung tumors characterized by oncogenic Q61R/L mutations in Kras. Functional: The passage implies that the KrasC118S mutation alters the molecular behavior of Kras in the context of tumorigenesis, as it is assessed for its impact on carcinogenesis and tumor development.

Gene→Variant (gene-first): 4843:C118S 3845:Q61R/L

Genes: 4843 3845

Variants: C118S Q61R/L

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the C118S mutation affects the ability of eNOS to stimulate the MAPK pathway and provides evidence of altered molecular function through immunoblot analysis of protein levels and activity. Oncogenic: The passage indicates that the C118S mutation is important for carcinogen-induced lung tumorigenesis, suggesting that it contributes to tumor development or progression.

Gene→Variant (gene-first): 4843:C118S 4843:G353>C 4846:S1177D

Genes: 4843 4846

Variants: C118S G353>C S1177D

[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the C118S mutation specifically blocks redox-dependent reactions that lead to Ras activation, indicating an alteration in molecular function. Oncogenic: The context of the study involves investigating the effect of the C118S mutation on Ras function during tumorigenesis, suggesting that this somatic variant contributes to tumor development or progression.

Gene→Variant (gene-first): 4843:C118 4843:C118S 4843:G353 transversion to C 4843:G353>C

Genes: 4843

Variants: C118 C118S G353 transversion to C G353>C

[Paragraph-level] PMCID: PMC2970593 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses mutations in the TK domain of EGFR that are critical for its activity, indicating that these variants alter molecular function related to protein activity. Oncogenic: The context of the mutations being in the TK domain of EGFR suggests that they may contribute to tumor development or progression, as this domain is often implicated in oncogenic signaling pathways.

Gene→Variant (gene-first): 1956:C797 NA:E734 NA:T785 1956:E868 1956:L858 1956:R831 NA:W731 1956:Y801

Genes: 1956 NA

Variants: C797 E734 T785 E868 L858 R831 W731 Y801

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 17

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the SF3B1 K700E variant contributes to cellular deficits characteristic of BRCA1/2 loss, indicating its role in tumor development or progression. Functional: The variant K700E is shown to alter the recruitment of Rad51 to replication forks and affects replication fork stability, demonstrating a change in molecular function.

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

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the SF3B1K700E variant affects replication fork dynamics and efficiency of replication fork restart, indicating an alteration in molecular function related to DNA replication. Oncogenic: The context of the study involves assessing the impact of the SF3B1K700E mutation on cellular processes relevant to tumor development, such as replication fork dynamics, which suggests a role in oncogenesis.

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

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The D210N variant is described as being catalytically inactivated, which alters its ability to resolve R-loops, indicating a change in molecular function. Oncogenic: The passage discusses the role of the D210N variant in the context of R-loop accumulation and genome instability, which are associated with tumor development and progression.

Gene→Variant (gene-first): 246243:D210N

Genes: 246243

Variants: D210N

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the K700E mutation alters molecular function by inducing unscheduled R-loops and affecting replication fork dynamics.

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

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the SF3B1K700E mutation alters the molecular function of homologous recombination (HR) by affecting the formation and resolution of Rad51 foci, indicating a defect in the later stages of HR. Oncogenic: The SF3B1K700E mutation is implicated in tumor development or progression as it affects the ability of cells to resolve recombination intermediates, which is a critical process in maintaining genomic stability in cancer cells.

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

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the SF3B1K700E variant alters the ability of cells to resolve DNA double-strand breaks (DSBs) and impairs homologous recombination (HR) repair, indicating a change in molecular function related to DNA repair mechanisms. Oncogenic: The SF3B1K700E mutation is described as cancer-associated and is shown to contribute to defects in DNA repair, which is a characteristic of oncogenic variants that promote tumor development or progression.

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

Genes: 23451

Variants: K700E

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

Evidence Type(s): Predictive, Functional

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

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

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC3184204 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predisposing, Diagnostic, Functional

Justification: Predisposing: The passage describes the discovery of the GATA2 gene as a predisposition gene for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), indicating that the variants are associated with inherited risk for developing these diseases. Diagnostic: The variants are used to define and classify familial forms of MDS and AML, as they are reported to segregate with the disease in multiple families, which supports their role in diagnosis. Functional: The passage mentions that the mutations have differential effects on transactivation of target genes, cellular differentiation, apoptosis, and global gene expression, indicating that they alter molecular or biochemical function.

Gene→Variant (gene-first): 2624:c.1061C>T 2624:c.1063_1065delACA 2624:p.Thr354Met 6688:p.Thr355del

Genes: 2624 6688

Variants: c.1061C>T c.1063_1065delACA p.Thr354Met p.Thr355del

[Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how various PTEN variants, including A126D, A126P, C124S, G129E, H123Q, P354Q, P38H, Q396R, R130L, and R130Q, alter the molecular function of PTEN by affecting pAKT levels, indicating changes in biochemical activity. Oncogenic: The variants are described in the context of their effects on the PI3-AKT signaling pathway and their ability to exhibit loss of function (LoF) or gain of function (GoF), which are indicative of their roles in tumor development or progression.

Gene→Variant (gene-first): 5728:A126D 5728:A126P 5728:C124S 5728:G129E 5728:H123Q 5728:P354Q 5728:P38H 5728:Q396R 5728:R130L 5728:R130Q

Genes: 5728

Variants: A126D A126P C124S G129E H123Q P354Q P38H Q396R R130L R130Q

[Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variants affect protein stability and abundance, indicating that they alter molecular function, which is supported by the use of western blot analysis and flow cytometry to measure these changes.

Gene→Variant (gene-first): 5728:H93Y 5728:P354Q 5728:R130L 5728:R14G 5728:R15S 5728:T78A

Genes: 5728

Variants: H93Y P354Q R130L R14G R15S T78A

[Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how PTEN variants affect sensorimotor neural circuit function and chemotaxis in C. elegans, indicating that these variants alter molecular or biochemical function. Oncogenic: The context of the passage suggests that the PTEN variants are involved in a pathway related to tumor development or progression, particularly given the focus on mutations in a cancer-related gene.

Gene→Variant (gene-first): 5728:A79T 5728:C124S 5728:D268E 5728:G132D 5728:P354Q 5728:T167N 5728:Y176C

Genes: 5728

Variants: A79T C124S D268E G132D P354Q T167N Y176C

[Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how various PTEN variants, including C124S, I101T, G132D, D268E, and A79T, alter neuronal growth processes and synapse density, indicating that these variants affect molecular or biochemical functions in neuronal cultures. Oncogenic: The passage mentions that the PHTS variant A79T exhibits a gain-of-function (GoF) phenotype in axonal growth, suggesting that it contributes to tumor development or progression in the context of its association with ASD.

Gene→Variant (gene-first): 5728:A79T 5728:C124S 5728:D268E 5728:G132D 5728:I101T

Genes: 5728

Variants: A79T C124S D268E G132D I101T

[Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how various PTEN variants, including C124S, G129E, N117S, and Q298E, alter developmental rates in Drosophila, indicating that these variants affect molecular or biochemical function related to insulin signaling and eclosion timing. Oncogenic: The mention of the known gain-of-function variant 4A inducing lethality suggests that some variants contribute to tumor development or progression, aligning with oncogenic behavior.

Gene→Variant (gene-first): 5728:C124S 5728:G129E 5728:N117S 5728:Q298E

Genes: 5728

Variants: C124S G129E N117S Q298E

[Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the C124S variant alters molecular interactions and functions within the context of PI3P metabolism and signaling, indicating a change in biochemical activity. Oncogenic: The C124S variant is described in the context of genetic interactions that may contribute to tumor development or progression, as it is involved in a synthetic dosage lethality screen related to PTEN's role in cancer biology.

Gene→Variant (gene-first): 5728:C124S

Genes: 5728

Variants: C124S

[Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 3

Evidence Type(s): Diagnostic, Oncogenic, Functional

Justification: Diagnostic: The passage discusses the classification of variants, including C124S, G129E, R130X, and R335X, in relation to their association with conditions such as ASD, PHTS, and somatic cancer, indicating their role in defining or confirming these diseases. Oncogenic: The passage mentions that C124S and G129E have been found in somatic cancer, indicating that these variants contribute to tumor development or progression. Functional: The passage describes several variants, including C124S and G129E, as having well-characterized disruptions on protein function, indicating that they alter molecular or biochemical function.

Gene→Variant (gene-first): 5728:C124S 5728:G129E 5728:R130X 5728:R335X 5728:Y138L

Genes: 5728

Variants: C124S G129E R130X R335X Y138L

[Paragraph-level] PMCID: PMC3973211 Section: RESULTS PassageIndex: 10

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the association between p53 mutations (R248, R282) and the expression of CYP3A4, a drug metabolism enzyme, indicating a correlation with drug clearance and potential response to chemotherapeutic drugs. Functional: The passage describes how p53 mutations (R248, R282) alter the expression levels of the CYP3A4 enzyme, demonstrating a change in molecular function related to drug metabolism.

Gene→Variant (gene-first): 7157:R175 7157:R175H 7157:R248 7157:R248W 7157:R273 7157:R273H 7157:R282 7157:R282W

Genes: 7157

Variants: R175 R175H R248 R248W R273 R273H R282 R282W

[Paragraph-level] PMCID: PMC3973211 Section: RESULTS PassageIndex: 8

Evidence Type(s): Prognostic, Functional

Justification: Prognostic: The passage mentions that R248Q/W and R282W are associated with mortality, indicating a correlation with disease outcome. Functional: The passage discusses the enrichment of specific gene sets linked to cellular respiration and drug metabolism enzymes for certain mutations, suggesting alterations in molecular function.

Gene→Variant (gene-first): 7157:R175H 7157:R248Q/W 7157:R248W 7157:R273H 7157:R282W

Genes: 7157

Variants: R175H R248Q/W R248W R273H R282W

[Paragraph-level] PMCID: PMC5481739 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the somatic DNMT3A-V716F mutation and its predicted effect on methyltransferase activity, indicating that the variant alters molecular function. Oncogenic: The mention of the somatic DNMT3A-V716F mutation in the context of a tumor suggests that it contributes to tumor development or progression.

Gene→Variant (gene-first): 1788:V716F

Genes: 1788

Variants: V716F

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 15

Evidence Type(s): Predictive, Oncogenic, Functional

Justification: Predictive: The passage discusses the response of KB1(L1363P)P mammary tumors to targeted therapies, indicating that these tumors responded significantly better to cisplatin and the PARP inhibitor AZD2461, which correlates the variant with treatment response. Oncogenic: The variant is associated with tumor development and progression, as it is discussed in the context of mammary tumors and their response to therapies, suggesting a role in cancer biology. Functional: The passage describes how the variant affects the ability of tumor cells to induce RAD51 foci in response to gamma-radiation, indicating an alteration in molecular function related to DNA repair mechanisms.

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

Genes: 7158

Variants: L1363P p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the Brca1 p.L1363P variant contributes to tumor formation and accelerates tumor development in a mouse model, indicating its role in tumor progression. Functional: The passage indicates that the Brca1 p.L1363P variant has a functional defect that compromises BRCA1-mediated homologous recombination repair (HRR), suggesting an alteration in molecular function.

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

Genes: 7158

Variants: L1363P p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses increased sensitivity to cisplatin and PARP1 inhibition in the context of the Brca1 p.L1363P variant, indicating a correlation with treatment response. Functional: The variant p.L1363P is shown to severely attenuate BRCA1-PALB2 binding, which alters the molecular function related to homologous recombination repair (HRR).

Gene→Variant (gene-first): 672:leucine to proline 7158:p.L1363P 672:p.L1407P

Genes: 672 7158

Variants: leucine to proline p.L1363P p.L1407P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional

Justification: Functional: The passage indicates that the variant p.L1363P alters the binding ability of BRCA1 to PALB2 and affects its activity in homologous recombination repair (HRR), demonstrating a change in molecular function.

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

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional

Justification: Functional: The passage discusses the evaluation of the functional consequences of the Brca1 p.L1363P variant, indicating that it alters molecular or biochemical function.

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

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses a functional analysis of the Brca1 p.L1363P variant, indicating that it alters embryonic development and leads to growth defects in mice, which demonstrates its impact on molecular or biochemical function. Oncogenic: The analysis of the Brca1 p.L1363P variant in the context of embryonic development and its comparison to Brca1-null mice suggests that it may contribute to tumor development or progression, as it is associated with severe phenotypes similar to pathogenic mutations in Brca1.

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

Genes: 7158

Variants: p.L1363P

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 672 7158

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

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 2261

Variants: K652E S249C Y375C

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

Evidence Type(s): Oncogenic, Functional

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

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

Genes: 5290 5163

Variants: E542K H1047L H1047R R115P

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

Evidence Type(s): Oncogenic, Functional

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

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

Genes: 5290

Variants: G1049R H1047R M1043I/L

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

Evidence Type(s): Functional

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

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

Genes: 5290

Variants: H1047R

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

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

Evidence Type(s): Functional

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

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

Genes: 5290

Variants: H1047R

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

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

Evidence Type(s): Oncogenic, Functional

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

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

Genes: 5290

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

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

Evidence Type(s): Oncogenic, Functional

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

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

Genes: 5290

Variants: H1047R His1047 Met1043

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

Evidence Type(s): Oncogenic, Functional

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

Gene→Variant (gene-first): 5290:E726K

Genes: 5290

Variants: E726K

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

Evidence Type(s): Functional

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

Gene→Variant (gene-first): 5290:N345K

Genes: 5290

Variants: N345K

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

Evidence Type(s): Oncogenic, Functional

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

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

Genes: 5290

Variants: G106V G118D N345K

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

Evidence Type(s): Functional

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

Gene→Variant (gene-first): 5290:D915N

Genes: 5290

Variants: D915N

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

Evidence Type(s): Predictive, Functional

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

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

Genes: 2322

Variants: D835 D835Y F691

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

Evidence Type(s): Oncogenic, Functional

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

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

Genes: 5290

Variants: H1047R

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

Evidence Type(s): Oncogenic, Predictive, Functional

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

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Functional, Oncogenic

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

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Functional

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

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Functional

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

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Predictive, Functional

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

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Functional

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

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Functional

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

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Functional, Oncogenic

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

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Functional, Oncogenic

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

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Functional, Oncogenic

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

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Oncogenic, Functional

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

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Oncogenic, Functional

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

Gene→Variant (gene-first): 324:V855A

Genes: 324

Variants: V855A

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 673 1956 324

Variants: L597V L858 L858R V855 V855A

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

Evidence Type(s): Oncogenic, Functional

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

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

Genes: 5604

Variants: p.K57N

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 2232 367 1387 10514 10499

Variants: G142V G524D M523V M537V M749I Q798E R629Q T575A

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

Evidence Type(s): Oncogenic, Functional

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

Gene→Variant (gene-first): 9611:M886I

Genes: 9611

Variants: M886I

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 367 1387 10514

Variants: H874Y M749I Q798E

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 2908 10499

Variants: I672 I672T R629 R629Q T575A

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 2232 367

Variants: G142V L57Q P390L P533S

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

Evidence Type(s): Functional

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

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

Genes: 367 10499

Variants: P390L R629Q T575A

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 10499 367

Variants: D879G H874Y Q919R T877A

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

Evidence Type(s): Predisposing, Functional

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

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

Genes: 367 9611

Variants: A765T K720E N756 Q902 Q902R R726L Y763C lysine 720

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 367 9611 1387 10514

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

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 367 9611

Variants: K910R M886 M886I

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

Evidence Type(s): Functional

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

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

Genes: 597 367 2908 10499

Variants: A586V A587S I672T R629Q T575A

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 2232 367

Variants: G142V G524D M523V M537V P533S

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 367 10514

Variants: P269S P390L P514S S515G

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 207 367 2232 9611

Variants: D221H D528G E198G P269S P340L P504L S296R S334P

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 1387 207 367 2232 9611

Variants: A234T D221H D528G E198G L57Q P340L P504L S296R S334P

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

Evidence Type(s): Functional, Oncogenic

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

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

Genes: 367

Variants: G166S M537R

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

Evidence Type(s): Functional

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

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

Genes: 2908 10499

Variants: I672 R629 T575

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

Evidence Type(s): Diagnostic, Functional

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

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

Genes: 1387 207 367 2232 10514

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