[Paragraph-level] PMCID: PMC7293710 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how the KRASG12V mutation correlates with increased sensitivity to the antiproliferation therapy of metformin, indicating a predictive relationship between the variant and treatment response. Oncogenic: The KRASG12V mutation is implicated in tumor development as it is mentioned in the context of its effect on cell viability and sensitivity to therapy in colorectal cancer cell lines.

Gene→Variant (gene-first): 3845:G12V

Genes: 3845

Variants: G12V

[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: 14

Evidence Type(s): Predictive

Justification: Predictive: The variant L1363P is associated with a response to cisplatin and PARP inhibition, indicating its correlation with treatment sensitivity.

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

Genes: 7158

Variants: L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 13

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses how KB1(L1363P)P mammary tumors are classified as predominantly carcinosarcomas, indicating that the variant is used to define and classify a specific tumor subtype. Oncogenic: The variant L1363P is associated with the development of carcinosarcomas, suggesting that it contributes to tumor progression and development, which aligns with oncogenic behavior.

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

Genes: 7158

Variants: L1363P p.L1363P

[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 12

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage indicates that the variant L1363P is associated with mammary tumors exhibiting EMT-like phenotypes, suggesting a role in tumor development or progression.

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

Genes: 7158

Variants: 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: 10

Evidence Type(s): Oncogenic

Justification: Oncogenic: The variant p.L1363P is associated with a defect in mammary tumor suppression, indicating its contribution to tumor development or progression.

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

Genes: 7158

Variants: 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: 4

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage indicates that the homozygous variant p.L1363P in Brca1 leads to embryonic lethality in mice, suggesting that it contributes to tumor development or progression.

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: PMC7612117 Section: RESULTS PassageIndex: 2

Evidence Type(s): None

Justification: Not enough information in this passage.

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

Genes: 7158

Variants: p.L1363P

[Paragraph-level] PMCID: PMC5822176 Section: RESULTS PassageIndex: 6

Evidence Type(s): Diagnostic

Justification: Diagnostic: The passage discusses the correlation of MIB-1 labeling indices with the diagnosis and grade of tumors, indicating that the K27M variant is associated with specific tumor classifications.

Gene→Variant (gene-first): 3417:K27M

Genes: 3417

Variants: K27M

[Paragraph-level] PMCID: PMC5822176 Section: RESULTS PassageIndex: 5

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 3417:K27M

Genes: 3417

Variants: K27M

[Paragraph-level] PMCID: PMC5822176 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses the transformation of tumors associated with the K27M variant, indicating its role in tumor development and progression, particularly in the context of glioblastoma transformation.

Gene→Variant (gene-first): 3417:K27M

Genes: 3417

Variants: K27M

[Paragraph-level] PMCID: PMC5822176 Section: RESULTS PassageIndex: 2

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the identification of H3 K27M-mutant tumors and provides demographic information, indicating that the variant is associated with specific histological diagnoses and patient characteristics. Oncogenic: The mention of H3 K27M in the context of tumors suggests that this somatic variant contributes to tumor development or progression, as it is identified in mutant tumors.

Gene→Variant (gene-first): 3417:K27M

Genes: 3417

Variants: K27M

[Paragraph-level] PMCID: PMC5822176 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Diagnostic, Prognostic, Oncogenic

Justification: Diagnostic: The passage discusses the H3 K27M mutation's association with various tumor types, indicating its role in defining and classifying these tumors, particularly in pediatric and adult cohorts. Prognostic: The passage mentions survival outcomes for patients with H3 K27M-mutant tumors, comparing mean survival times between adults and pediatric patients, which indicates a correlation with disease outcome. Oncogenic: The H3 K27M mutation is described as contributing to tumor development in various glioma types, indicating its role as a somatic variant involved in tumor progression.

Gene→Variant (gene-first): 3417:K27M

Genes: 3417

Variants: K27M

[Paragraph-level] PMCID: PMC3288377 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the frequency of the p.K27M mutation in DIPGs and its association with this specific subtype of brain tumors, indicating its role in defining or classifying the disease. Oncogenic: The p.K27M and p.G34R mutations are described as somatic mutations found in pediatric gliomas, suggesting their contribution to tumor development or progression.

Gene→Variant (gene-first): 3021:p.G34R 3021:p.K27M

Genes: 3021

Variants: p.G34R p.K27M

[Paragraph-level] PMCID: PMC6368247 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the emergence of the ESR1 Y537S mutation in the context of resistance to CDK4/6 inhibitors, indicating a correlation with treatment response and resistance. Oncogenic: The mention of the ESR1 Y537S mutation as a new driver mutation suggests that it contributes to tumor development or progression, particularly in the context of breast cancer.

Gene→Variant (gene-first): 5728:Y537S

Genes: 5728

Variants: Y537S

[Paragraph-level] PMCID: PMC5122709 Section: RESULTS PassageIndex: 3

Evidence Type(s): Predictive, Diagnostic, Oncogenic

Justification: Predictive: The passage discusses patients treated with BRAF inhibitors, specifically mentioning the BRAF V600E mutation, which correlates with response to these therapies. Diagnostic: The passage states that all patients tested positive for the BRAF V600E mutation, indicating its use in defining or confirming the presence of a specific subtype of melanoma. Oncogenic: The BRAF V600E mutation is implicated in the development of melanoma, suggesting its role as a somatic variant contributing to tumor progression.

Gene→Variant (gene-first): 673:V600E

Genes: 673

Variants: V600E

[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: PMC7099049 Section: ABSTRACT PassageIndex: 4

Evidence Type(s): Prognostic

Justification: Prognostic: The passage indicates that the SNPs are suggested to play a crucial role in the prognosis of HNSCC, which correlates with disease outcome.

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

Genes: NA 388325 341019

Variants: rs16879870 rs2641256 rs2761591 rs854936

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

Evidence Type(s): Prognostic, Functional

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

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

Genes: NA 388325 341019

Variants: rs16879870 rs2641256 rs2761591 rs854936

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

Evidence Type(s): Predictive, Functional

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

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

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC9900321 Section: ABSTRACT PassageIndex: 3

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in treating pancreatic ductal adenocarcinoma, indicating a correlation between the Gly-to-Asp mutation and response to therapy. Oncogenic: The Gly-to-Asp mutation in the KRAS oncogene is described as contributing to tumor development in pancreatic ductal adenocarcinoma, as it is found in more than 90% of patients with this cancer type.

Gene→Variant (gene-first): 3845:Gly-to-Asp

Genes: 3845

Variants: Gly-to-Asp

[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: PMC4999563 Section: ABSTRACT PassageIndex: 9

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The passage indicates that KRAS G12C and G13D mutations are associated with inferior progression-free survival (PFS) and overall survival (OS) in mCRC patients, suggesting a correlation with disease outcome independent of therapy. Diagnostic: The mention of KRAS mutations being associated with heterogeneous outcomes compared to unmutated tumors implies that these variants can be used to classify or define a disease subtype in mCRC.

Gene→Variant (gene-first): 3845:G12C 3845:G13D

Genes: 3845

Variants: G12C G13D

[Paragraph-level] PMCID: PMC4999563 Section: ABSTRACT PassageIndex: 7

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The passage discusses the correlation of KRAS mutations, including specific variants like G12C and G13D, with inferior overall survival (OS) and progression-free survival (PFS), indicating their impact on disease outcome independent of therapy. Diagnostic: The passage mentions that mutations in KRAS were diagnosed in tumors, indicating that these mutations are used to classify or define the disease.

Gene→Variant (gene-first): 3845:G12C 3845:G12D 3845:G12V 3845:G13D

Genes: 3845

Variants: G12C G12D G12V G13D

[Paragraph-level] PMCID: PMC4999563 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The passage discusses how KRAS G12C and G13D mutations correlate with inferior progression-free and overall survival in metastatic colorectal cancer patients, indicating their prognostic significance. Diagnostic: The mention of KRAS mutations being associated with tumor characteristics suggests their role in classifying or defining the disease subtype in colorectal cancer.

Gene→Variant (gene-first): 3845:G12C 3845:G13D

Genes: 3845

Variants: G12C G13D

[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: PMC6280667 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive

Justification: Predictive: The passage discusses the correlation of mutations, including those in splicing components like ZRSR2, with sensitivity to various drugs, indicating a relationship between the variant and treatment response.

Gene→Variant (gene-first): 8233:serine/arginine

Genes: 8233

Variants: serine/arginine

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 17

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses the tumor forming capacity of cells expressing the ERBB2 E401G variant, indicating that this somatic variant contributes to tumor development as evidenced by increased tumor growth in vivo.

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: 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: 15

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

[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: 11

Evidence Type(s): None

Justification: Not enough information in this passage.

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: PMC8881279 Section: RESULTS PassageIndex: 2

Evidence Type(s): Diagnostic

Justification: Diagnostic: The passage mentions the detection of the ERBB2 E401G variant of uncertain significance (VUS) in a patient, indicating its use in defining or classifying a disease context, specifically in a patient with cancer of unknown primary (CUP).

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

[Paragraph-level] PMCID: PMC6938308 Section: RESULTS PassageIndex: 2

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage indicates that KRAS codon p.12G and BRAF codon p.600V somatic mutations have been linked to brain AVMs, suggesting their role in defining or classifying the disease. Oncogenic: The mention of likely somatic disease-causing mutations, including KRAS mutations (p.G12D and p.G12V) and BRAF mutations (p.V600E and p.Q636X), indicates that these variants contribute to tumor development or progression.

Gene→Variant (gene-first): 3845:p.12G 673:p.600V 3845:p.G12D 3845:p.G12V 673:p.Q636X 673:p.V600E

Genes: 3845 673

Variants: p.12G p.600V p.G12D p.G12V p.Q636X p.V600E

[Paragraph-level] PMCID: PMC8307492 Section: ABSTRACT PassageIndex: 4

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the association of the L858R variant with overall survival (OS) in patients treated with first-line EGFR inhibitors, indicating its relevance to treatment response. Oncogenic: The L858R variant is mentioned in the context of EGFR mutations in non-small-cell lung cancer (NSCLC), suggesting its role in tumor development or progression as part of the broader analysis of clinically actionable EGFR mutations.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC10805385 Section: RESULTS PassageIndex: 17

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The passage discusses the overexpression of HOXC10 in KRAS-mutant tumors, specifically mentioning the genotype KRAS G12C/TP53 G245V, indicating that these somatic variants contribute to tumor development or progression. Predictive: The passage mentions the efficacy of combined MEK/BET inhibitors causing tumor regression in KRAS-mutant patient-derived xenograft models, suggesting a correlation between the variants and response to therapy.

Gene→Variant (gene-first): 3845:G12C 7157:G245V

Genes: 3845 7157

Variants: G12C G245V

[Paragraph-level] PMCID: PMC10690049 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of KRASG12D mutant MEFs to a drug combination, indicating that the variant is associated with resistance to growth inhibition by the therapies tested. Oncogenic: The KRASG12D variant is implicated in tumor behavior, as it is described in the context of MEFs (mouse embryonic fibroblasts) and their growth characteristics, suggesting a role in tumor development or progression.

Gene→Variant (gene-first): 3845:G12D

Genes: 3845

Variants: G12D

[Paragraph-level] PMCID: PMC10690049 Section: RESULTS PassageIndex: 6

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of KRAS G12C-mutant cells to specific therapies, indicating a correlation between the variant and sensitivity to the drugs MRTX849/AMG510 and KPT9274. Oncogenic: The variant KRAS G12C is implicated in tumor development, as the passage describes its presence in cancer cell lines and their proliferation in response to treatment, suggesting a role in cancer progression.

Gene→Variant (gene-first): 3845:G12C

Genes: 3845

Variants: G12C

nan evidence:

Missing abstract

Predictive, Diagnostic, Oncogenic evidence:

Predictive: The abstract mentions that NF1 mutant melanomas can be effectively treated with EGFR inhibitors, indicating a correlation between the variant and response to therapy.

Diagnostic: The results section describes the identification of mutational profiles in melanoma samples, specifically noting that C>T transitions are characteristic of cutaneous melanoma, which supports the use of this variant in defining the disease subtype.

Oncogenic: The results highlight that the C>T transitions are part of the mutational spectra associated with cutaneous melanoma, suggesting that these somatic variants contribute to tumor development or progression.

Diagnostic, Oncogenic evidence:

Diagnostic: The study mentions that six (4%) of the GBM tumors were IDH1 p.R132H-mutated, indicating that this variant is used to classify or confirm a specific subtype of the disease, which aligns with the definition of a diagnostic evidence type.

Oncogenic: The presence of the IDH1 p.R132H mutation in the tumors suggests that this somatic variant contributes to tumor development or progression, which is characteristic of oncogenic evidence.

nan evidence:

Based on the provided abstract and results section, there is no specific mention of any variants or their implications. Therefore, I cannot classify any evidence types as there are no relevant statements to support any of the CIViC evidence types.

Diagnostic, Functional evidence:

Diagnostic: The abstract discusses the improvement in the accuracy of diagnosis for diffuse gliomas, indicating that the study evaluates genetic/clinical correlations, which may include the variant C228T as part of the diagnostic criteria for glioma classification.

Functional: The results section mentions the mutational analysis of the TERT promoter, specifically referring to the C228T variant, which implies that this variant is being analyzed for its molecular characteristics, such as its role in the context of tumor genetics.

nan evidence:

Missing abstract

Predictive, Functional evidence:

Functional: The study discusses how the mispairing of guanine with thymine during DNA replication, specifically the O6-meG/T mismatch, alters the cellular response to temozolomide treatment by initiating futile cycles of the mismatch repair machinery, leading to DNA damage and cell death. This indicates a change in molecular function due to the variant's presence.

Predictive: The abstract mentions that promoter methylation-mediated silencing of MGMT is associated with increased sensitivity towards temozolomide, suggesting that the guanine-thymine mispairing impacts the response to this specific therapy. This correlation indicates a predictive relationship between the variant and treatment outcome.

nan evidence:

There is no information provided in the abstract or results section regarding the variant(s) mentioned in the paper. Therefore, I cannot classify any evidence types based on the given text.

Diagnostic, Oncogenic evidence:

Diagnostic: The study identifies a de novo pathogenic variant in ELOC (c.236A>G, p.Tyr79Cys) in a proband with VHL disease, suggesting that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease who do not have detectable VHL variants. This indicates the variant's role in classifying or confirming the disease.

Oncogenic: The p.Tyr79Cys substitution is described as a mutational hotspot in sporadic VHL-competent RCC and has been shown to mimic the effects of pVHL deficiency on hypoxic signaling, indicating its contribution to tumor development or progression. This supports the classification of the variant as oncogenic due to its association with cancer-related mechanisms.

Predictive, Oncogenic evidence:

Predictive: The study indicates that AR gene rearrangements in CRPC tumors are associated with resistance to endocrine therapies, specifically mentioning that cell lines with these rearrangements were resistant to the AR antagonist enzalutamide. This suggests a correlation between the variant and treatment response, classifying it as predictive evidence.

Oncogenic: The abstract describes AR gene rearrangements as contributing to the development and progression of CRPC, highlighting their role in promoting the expression of tumor-specific AR variants. This supports the classification of the variant as oncogenic due to its involvement in tumor development.

Predictive, Oncogenic evidence:

Predictive: The study indicates that AR gene rearrangements in CRPC tumors are associated with resistance to endocrine therapies, specifically mentioning that cell lines with these rearrangements were resistant to the AR antagonist enzalutamide. This suggests a correlation between the variant and treatment response, classifying it as predictive evidence.

Oncogenic: The abstract describes AR gene rearrangements as contributing to the development and progression of CRPC, highlighting their role in promoting the expression of tumor-specific AR variants. This supports the classification of the variant as oncogenic due to its involvement in tumor development.

Predictive, Oncogenic evidence:

Predictive: The study indicates that AR gene rearrangements in CRPC tumors are associated with resistance to endocrine therapies, specifically mentioning that cell lines with these rearrangements were resistant to the AR antagonist enzalutamide. This suggests a correlation between the variant and treatment response, classifying it as predictive evidence.

Oncogenic: The abstract states that AR gene rearrangements contribute to the development and progression of CRPC, highlighting their role in tumor-specific AR variant expression. This supports the classification of the variant as oncogenic due to its involvement in tumor development.

Oncogenic evidence:

Oncogenic: The study identifies the 1520C>A mutation (T507K) in the PTPN11 gene as contributing to tumor development, as evidenced by its ability to induce transformed foci in NIH3T3 cells and promote tumor formation in nude mice, indicating its role as an oncoprotein in solid tumors.

Diagnostic evidence:

Diagnostic: The study discusses the potential diagnostic utility of the TRPS1::PLAG1 fusion for determining tumor origin, indicating that this variant can help classify and identify the type of tumor present. The mention of recurrent gene fusions in CMTs and their association with specific histological features further supports its role in disease classification.

Oncogenic evidence:

Oncogenic: The study identifies structural rearrangements involving the PLAG1 gene in chondroid syringomas, specifically the formation of NDRG1-PLAG1 and TRPS1-PLAG1 fusion transcripts, which suggests that these somatic variants contribute to tumor development or progression.

Oncogenic evidence:

Oncogenic: The study identifies structural rearrangements involving the PLAG1 gene in chondroid syringomas, specifically the NDRG1-PLAG1 and TRPS1-PLAG1 fusion transcripts, indicating that these somatic variants contribute to tumor development. The presence of these fusion genes suggests a role in the oncogenic process associated with this type of tumor.

Predictive, Oncogenic evidence:

Predictive: The variant FGFR1 p.V561M is described as imparting resistance to FGFR inhibitors, indicating its role in predicting treatment response and resistance to therapy in the context of pilomyxoid astrocytomas.

Oncogenic: The study identifies the FGFR1 p.V561M variant as a gatekeeper mutation that contributes to tumor development by imparting resistance to inhibitors, suggesting its role in the oncogenic process of pilomyxoid astrocytomas.

Predictive, Oncogenic evidence:

Predictive: The variant FGFR1 p.V561M is described as imparting resistance to FGFR inhibitors, indicating its role in predicting treatment response and resistance in the context of therapy for pilomyxoid astrocytomas.

Oncogenic: The study identifies the FGFR1 p.V561M variant as a gatekeeper mutation that contributes to the tumor's characteristics, suggesting its involvement in tumor development or progression.

nan evidence:

Missing abstract

Predictive, Diagnostic evidence:

Diagnostic: The study discusses the use of FISH analysis for screening ABL1 fusions in pediatric acute lymphoblastic leukemia (ALL), indicating that the presence of the NUP214-ABL1 fusion can be used to classify or confirm the disease. This suggests that the variant is associated with a specific subtype of leukemia, fulfilling the criteria for diagnostic evidence.

Predictive: The abstract mentions that ABL1 fusions are potentially targetable by kinase inhibitors, indicating a correlation between the presence of this variant and the response to specific therapies. This aligns with predictive evidence as it suggests that the variant may influence treatment options.

Functional evidence:

Functional: The variant p.Ser695Leu in EZH2 is mentioned in the context of sequencing results, indicating that it is a mutation found in the patient. This suggests that the variant may alter the molecular function of the EZH2 protein, which is relevant to its role in cancer biology.

nan evidence:

Missing abstract

Oncogenic evidence:

Oncogenic: The study 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, particularly in the context of PARPi-resistant cell lines. This suggests that the variant contributes to the oncogenic processes in these cancer cells.

Predictive, Diagnostic evidence:

Predictive: The study discusses the addition of pembrolizumab to chemotherapy and its impact on disease-free survival (DFS) in patients with dMMR endometrial cancer, indicating a correlation between the dMMR phenotype and treatment response. The results show a significant hazard ratio for DFS in the dMMR population, suggesting that the variant's presence may predict a better response to the therapy.

Diagnostic: The abstract mentions the classification of patients based on their dMMR status, which is used to define a specific subtype of endometrial cancer. This indicates that the dMMR variant is associated with a particular disease phenotype, supporting its role as a diagnostic marker.

Predictive, Prognostic evidence:

Predictive: The study reports that patients with dMMR/MSI-H endometrial cancer treated with dostarlimab plus carboplatin-paclitaxel had a statistically significant reduction in the risk of death, indicating that the variant correlates with response to this specific therapy. The mention of hazard ratios and the context of treatment response supports this classification.

Prognostic: The results indicate a statistically significant overall survival benefit in patients treated with dostarlimab, with a specific hazard ratio reported for the dMMR/MSI-H population, suggesting that the variant correlates with disease outcome independent of therapy. This aligns with the definition of prognostic evidence.

Predictive, Prognostic evidence:

Predictive: The study discusses the significant increase in progression-free survival among patients with dMMR-MSI-H tumors treated with dostarlimab, indicating that the variant correlates with response to this specific therapy. The results show a marked difference in progression-free survival rates between the dostarlimab and placebo groups, highlighting the predictive nature of the variant in relation to treatment efficacy.

Prognostic: The results also provide data on overall survival rates at 24 months, suggesting that the presence of the dMMR-MSI-H variant correlates with better survival outcomes independent of therapy. The hazard ratios reported for both progression-free survival and overall survival indicate that this variant has prognostic implications for patients with endometrial cancer.

Predictive, Oncogenic evidence:

Predictive: The study discusses how alterations in specific tumor suppressor genes, including the Kras G12D variant, can identify patients likely to benefit from immune checkpoint inhibitors combined with chemotherapy, indicating a correlation with treatment response.

Oncogenic: The variant Kras G12D is part of a genetically engineered model used to assess its role in promoting tumor growth, demonstrating its contribution to tumor development in the context of lung cancer.

Predictive, Diagnostic evidence:

Predictive: The study investigates the efficacy of Debio 1347, a selective inhibitor targeting FGFR1-3 fusions, in patients with solid tumors harboring these fusions, indicating a focus on treatment response. The mention of "objective response rate (ORR)" and the evaluation of efficacy directly relates to the predictive nature of the variant's impact on therapy response.

Diagnostic: The abstract states that the trial involved patients with tumors "harboring a functional FGFR1-3 fusion," which implies that the presence of these fusions is used to classify or define the patient population for the study, thus supporting a diagnostic classification.

Predictive, Diagnostic evidence:

Diagnostic: The study discusses the t(4;14) translocation as a characteristic found in approximately 15% of patients with multiple myeloma, indicating its role in classifying patients based on their genetic status. This classification is essential for understanding the disease and tailoring treatment approaches.

Predictive: The study evaluates the efficacy of dovitinib, an RTK inhibitor, in patients with relapsed or refractory multiple myeloma, specifically assessing the treatment response based on the presence of the t(4;14) translocation. The mention of treatment response rates in relation to the t(4;14) status suggests a predictive relationship between the variant and therapy outcomes.

Predictive, Oncogenic evidence:

Predictive: The study discusses the efficacy of fexagratinib, an FGFR inhibitor, in patients with recurrent FGFR-TACC + high-grade gliomas, indicating a correlation between the FGFR-TACC fusion and response to this specific therapy. The mention of a 32-gene signature associated with the benefit of FGFR inhibition further supports the predictive nature of the variant in relation to treatment response.

Oncogenic: The abstract states that FGFR-TACC fusions are oncogenic and present in high-grade gliomas, indicating that these somatic variants contribute to tumor development or progression. This classification is supported by the context of the study focusing on the safety and efficacy of a treatment targeting these specific fusions.

Oncogenic evidence:

Oncogenic: The variant K27M is associated with the histone H3 K27M mutant protein, which is known to contribute to tumor development or progression in certain cancers, particularly gliomas. The mention of this specific mutant protein in the results section indicates its role in oncogenesis.

Diagnostic evidence:

Diagnostic: The abstract discusses HGAP as an important consideration in the differential diagnosis of isocitrate dehydrogenase-wild-type gliomas, indicating that the variant is used to classify or define a disease subtype. Additionally, it mentions the association with neurofibromatosis 1 syndrome, further supporting its role in diagnosis.

Diagnostic, Predisposing evidence:

Diagnostic: The study discusses the identification of germline mutations in patients with pheochromocytomas and paragangliomas (PPGLs), indicating that these variants can lead to an early diagnosis of multiple or more aggressive tumors, which aligns with the use of variants to define or confirm a disease.

Predisposing: The mention of germline mutations in patients with PPGLs suggests an inherited risk for developing these tumors, particularly in younger patients, which supports the classification of these variants as predisposing.

Predictive, Prognostic, Oncogenic evidence:

Predictive: The study discusses the variant G2032R in the context of acquired resistance mutations, indicating that taletrectinib shows robust activity against this variant, which correlates with treatment response. This suggests that the presence of G2032R may influence the effectiveness of taletrectinib therapy in patients with NSCLC.

Prognostic: The results mention prolonged progression-free survival associated with taletrectinib treatment, which implies that the presence of the G2032R variant may correlate with disease outcome independent of therapy. This indicates that the variant could have implications for patient prognosis in the context of treatment with taletrectinib.

Oncogenic: The mention of G2032R as an acquired resistance mutation suggests that it contributes to tumor progression or development, particularly in the context of resistance to therapy. This aligns with the definition of an oncogenic variant, as it is involved in the cancer's response to treatment.

Predictive, Oncogenic evidence:

Predictive: The study discusses the drug sensitivity and resistance of the exon 20 insertion variants, specifically mentioning that they have lower sensitivity to 1st-3rd generation EGFR TKIs and that newer inhibitors like BAY-568, TAS6417, and TAK-788 show selective inhibition, indicating a correlation with treatment response.

Oncogenic: The abstract highlights that somatic mutations in EGFR, including the exon 20 insertions, are frequent drivers of non-small cell lung cancer (NSCLC), which supports the notion that these variants contribute to tumor development and progression.

Predictive evidence:

Predictive: The study demonstrates that treatment with osimertinib significantly improves progression-free survival in patients with unresectable EGFR-mutated NSCLC, indicating a correlation between the EGFR mutation and response to this specific therapy. The results show a median progression-free survival of 39.1 months with osimertinib compared to 5.6 months with placebo, highlighting the predictive nature of the EGFR variant in treatment outcomes.

Predictive, Diagnostic evidence:

Diagnostic: The variant M34 is associated with the pathology diagnosis of LUSC (lung squamous cell carcinoma) in the context of the study, indicating its relevance in defining or classifying this disease subtype.

Predictive: The results indicate that patients with the M34 variant received first-line treatment with chemo+pembrolizumab, and the best response was complete response (CR), suggesting a correlation between this variant and treatment response.

Prognostic, Functional evidence:

Prognostic: The abstract mentions that "Osteosarcoma (OS) patients with metastasis or recurrent tumors still suffer from poor prognosis," indicating a correlation between the variant and disease outcome independent of therapy.

Functional: The study discusses how treatment with the DNA demethylating agent 5-aza-2'-deoxycytidine (5-aza-dC) "markedly suppressed their growth" and "multiple tumor-suppressor and osteo/chondrogenesis-related genes were re-activated," suggesting that the variant alters molecular function related to gene expression and cellular behavior.

Predictive evidence:

Predictive: The abstract indicates that selective TRK inhibition by larotrectinib is a therapeutic option specifically for IFS carrying the ETV6-NTRK3 gene fusion, suggesting a correlation between this variant and response to therapy. This aligns with the definition of predictive evidence, as it discusses the effectiveness of a treatment based on the presence of a specific variant.

Diagnostic, Prognostic evidence:

Diagnostic: The study discusses kataegis in the context of breast cancer subgroups defined by ER, PR, and HER2/ERBB2 status, indicating its role in classifying and associating with specific tumor characteristics and aggressive phenotypes.

Prognostic: The abstract mentions that kataegis status was associated with aggressive characteristics in certain breast cancer subgroups, suggesting a correlation with disease outcome, particularly in ERpHER2n tumors.

Predictive, Diagnostic evidence:

Diagnostic: The study identifies the Ph-like gene expression profile and its association with specific genomic alterations in childhood B-lineage ALL, indicating that these genetic lesions can be used to classify and define this high-risk subtype of leukemia.

Predictive: The findings suggest that the identified targetable genetic lesions, such as CRLF2 rearrangements and ABL-class fusions, may correlate with treatment approaches in precision medicine for Ph-like ALL, indicating their potential role in predicting response to targeted therapies.

Predictive, Diagnostic evidence:

Diagnostic: The study identifies the Ph-like gene expression profile and its association with high-risk childhood B-lineage ALL, indicating that specific genetic alterations can be used to classify and define this subtype of leukemia.

Predictive: The findings suggest that the identified targetable genetic lesions, such as CRLF2 rearrangements and ABL-class fusions, may correlate with treatment approaches in precision medicine for Ph-like ALL, indicating potential sensitivity to specific therapies.

Predictive, Diagnostic evidence:

Diagnostic: The study identifies the Ph-like gene expression profile and its association with specific genetic alterations in childhood B-lineage ALL, indicating its role in classifying this high-risk subtype of leukemia.

Predictive: The findings support a precision-medicine approach for Ph-like ALL, suggesting that the identified genetic lesions may correlate with response to targeted therapies, which is a key aspect of treatment for this subtype.

Predictive, Diagnostic evidence:

Diagnostic: The study identifies the Ph-like gene expression profile and its association with specific genetic alterations in childhood B-lineage ALL, indicating its role in classifying this high-risk subtype of leukemia. The mention of the frequency of CRLF2 rearrangements and other genetic lesions further supports the use of these variants in defining the disease.

Predictive: The findings suggest that the identified genetic alterations, including CRLF2 rearrangements and other targetable lesions, may correlate with treatment approaches in precision medicine for Ph-like ALL, indicating their potential impact on therapy response. The emphasis on targetable genetic lesions implies a relationship with treatment strategies.

Predictive, Diagnostic evidence:

Diagnostic: The study identifies the Ph-like gene expression profile and its association with high-risk childhood B-lineage ALL, indicating that specific genomic alterations can be used to classify and define this subtype of leukemia.

Predictive: The findings suggest that the identified targetable genetic lesions, such as CRLF2 rearrangements and ABL-class fusions, may correlate with treatment approaches in precision medicine for Ph-like ALL, indicating potential sensitivity to specific therapies.

Predictive, Diagnostic evidence:

Diagnostic: The study identifies the Ph-like gene expression profile and its association with specific genetic alterations in childhood B-lineage ALL, indicating that these variants can be used to classify and define this high-risk subtype of leukemia.

Predictive: The findings suggest that the identified genetic lesions, including CRLF2 rearrangements and other targetable alterations, may correlate with treatment response in the context of precision medicine for Ph-like ALL, highlighting their potential role in guiding therapy.

Predictive, Diagnostic evidence:

Diagnostic: The study identifies the Ph-like gene expression profile and its association with specific genetic alterations in childhood B-lineage ALL, indicating its role in classifying this high-risk subtype of leukemia. The mention of the frequency of CRLF2 rearrangements and other genomic alterations further supports the use of these variants in defining the disease.

Predictive: The findings suggest that the identified genetic lesions, including CRLF2 rearrangements and other targetable alterations, may correlate with treatment approaches in precision medicine for Ph-like ALL, indicating their potential impact on therapy response. The emphasis on targetable genetic lesions implies a relationship with treatment strategies.

Diagnostic, Prognostic evidence:

Prognostic: The study reports that higher numbers of somatic mutations and copy number alterations (CNAs) significantly correlated with worse survival, indicating that these genetic alterations are associated with disease outcomes independent of therapy. Additionally, it identifies specific mutations and amplifications, such as PD-L1, as independent poor prognostic factors in aggressive ATL, further supporting the prognostic nature of these findings.

Diagnostic: The abstract mentions that aggressive and indolent ATL subtypes are associated with different genetic alterations, which helps classify the disease into molecularly distinct subsets. This classification based on genetic profiles indicates the use of these variants in defining and understanding the disease subtypes.

Predictive, Oncogenic evidence:

Predictive: The study discusses the association of the L858R mutation with treatment outcomes, indicating that patients with this mutation have a similar overall survival (OS) compared to those with uncommon, actionable variants when treated with first-line EGFR inhibitors. This suggests that the presence of the L858R variant correlates with response to therapy, which is a key aspect of predictive evidence.

Oncogenic: The abstract mentions that activating mutations in EGFR, including L858R, are a common mechanism of malignant transformation in non-small cell lung cancer (NSCLC). This indicates that the L858R variant contributes to tumor development, supporting its classification as oncogenic.

Predictive, Prognostic evidence:

Predictive: The abstract mentions that testing for driver mutations identifies patients who benefit from TKI-therapy, indicating that the presence of such mutations, including T790M, correlates with response to specific therapies. Additionally, the results highlight that the presence of a driver mutation predicts response to specific TKIs, further supporting the predictive nature of the T790M variant in the context of treatment.

Prognostic: The results section states that EGFR-positive NSCLC is associated with improved prognosis, suggesting that the presence of the T790M variant may correlate with disease outcomes independent of therapy. This indicates that T790M could have prognostic implications in the context of NSCLC.

Diagnostic, Oncogenic evidence:

Diagnostic: The variant p.V617F is mentioned as a major diagnostic criterion for the diagnosis of Polycythemia Vera (PV), indicating its role in defining and confirming the disease. The presence of this mutation is used to classify the disease, which aligns with the definition of a diagnostic evidence type.

Oncogenic: The mention of the JAK2 p.V617F mutation in the context of diagnostic criteria for PV suggests that it contributes to tumor development or progression, as it is a well-known somatic mutation associated with myeloproliferative neoplasms. This aligns with the oncogenic evidence type, as it indicates the variant's role in the pathogenesis of the disease.

nan evidence:

Parsing error: argument of type 'NoneType' is not iterable

Predictive, Diagnostic evidence:

Diagnostic: The study evaluates the immunophenotypes and karyotypes of patients with childhood acute lymphoblastic leukemia (ALL) associated with the t(1;19) and der(19)t(1;19) translocations, suggesting that these variants can be used to classify distinct subtypes of ALL.

Predictive: The results indicate that patients with the t(1;19) and der(19)t(1;19) translocations did not respond to therapy as well as those with early pre-B ALL, highlighting the predictive nature of these variants in terms of treatment response.

Predictive, Diagnostic evidence:

Predictive: The identification of the COL1A1-PDGFB gene fusion allows greater choice of targeted therapy in these patients, indicating that the variant correlates with response to specific therapies.

Diagnostic: The COL1A1-PDGFB gene fusion is associated with a specific subtype of uterine sarcoma, which supports its use in defining and classifying this disease entity.

Predictive, Diagnostic evidence:

Diagnostic: The study identifies the SH3PXD2A::HTRA1 fusion in schwannomas and discusses its prevalence and association with specific clinicopathologic characteristics, indicating its role in defining and classifying these tumors. The mention of "fusion-positive schwannomas" and their distinct features supports the classification of this variant as a diagnostic marker.

Predictive: The study establishes a correlation between the presence of the SH3PXD2A::HTRA1 fusion and specific histological features, such as the 'serpentine' palisading pattern, which can predict fusion status with high sensitivity and specificity. This suggests that the variant may be used to predict certain characteristics of the tumors, aligning with predictive evidence.

nan evidence:

Based on the provided information, there are no mentions of the variant in either the abstract or the results section. Therefore, I cannot classify any evidence type as there is no supporting text to justify a classification.

nan evidence:

Parsing error: argument of type 'NoneType' is not iterable

Diagnostic, Oncogenic evidence:

Oncogenic: The abstract discusses the identification of EGFR internal tandem duplications (ITD) in tumors, specifically noting their presence in congenital mesoblastic nephromas and other pediatric sarcomas. This suggests that the EGFR ITD contributes to tumor development or progression in these specific cancer types.

Diagnostic: The study highlights the association of EGFR ITD with specific tumor types, particularly in pediatric sarcomas, indicating its role in defining or classifying these tumors. The identification of this variant in a subset of tumors supports its use as a biomarker for diagnosis.

Prognostic evidence:

Prognostic: The study indicates that adult patients with t(1;19)(q23;p13) positive ALL had a favorable prognosis, as evidenced by the reported 5-year cumulative incidence of relapse and overall survival rates. This suggests that the variant correlates with disease outcome independent of therapy.

Diagnostic, Prognostic evidence:

Prognostic: The study indicates that the t(1;19) variant is an independent risk factor for isolated CNS relapse, suggesting that it correlates with disease outcome independent of therapy. This is supported by the mention of event-free survival and the cumulative incidence of relapse in patients with this variant.

Diagnostic: The t(1;19) is used to classify and define a specific subtype of B-cell precursor acute lymphoblastic leukemia (ALL), as indicated by its association with the TCF3/PBX1 fusion. This classification is crucial for understanding the disease and its treatment implications.

Diagnostic, Oncogenic evidence:

Diagnostic: The study discusses the t(1;19) chromosomal translocation as being observed in 25% of children with pre-B-cell acute lymphoblastic leukemia (ALL) and highlights its association with an adverse treatment outcome, indicating its role in defining and classifying the disease. The detection of E2A/PBX1 fusion transcripts in a majority of cases further supports its use as a biomarker for this subtype of leukemia.

Oncogenic: The findings suggest that the E2A/PBX1 fusion resulting from the t(1;19) translocation is an important pathogenic event in t(1;19) ALL, indicating that this somatic variant contributes to tumor development or progression in this specific leukemia type.

Diagnostic, Oncogenic evidence:

Diagnostic: The study discusses the t(1;19) translocation and its association with acute lymphoblastic leukemia (ALL), indicating that it is a common genetic alteration used to classify the disease. The mention of different mechanisms leading to the formation of the der(19) and the investigation of markers proximal to the breakpoint further supports its role in defining the disease subtype.

Oncogenic: The t(1;19) translocation is described as one of the most common translocations in ALL, suggesting that it contributes to tumor development or progression. The study's focus on the mechanisms of how the der(19) arises indicates its potential role in oncogenesis within the context of leukemia.

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Predictive, Diagnostic evidence:

Diagnostic: The study discusses the identification of patients with E2A-PBX1 positive translocations, indicating that the presence of this specific variant is used to classify and confirm a subtype of acute lymphoblastic leukemia (ALL). The development of a fluorescence in situ hybridization assay to detect E2A translocations further supports its role as a diagnostic tool in identifying patients who require specific therapeutic interventions.

Predictive: The abstract mentions that more intensive therapy improves the outcome of patients with E2A-PBX1 positive translocations, suggesting that the presence of this variant correlates with response to therapy. This highlights the importance of identifying this subset of patients to administer appropriate treatment, which aligns with predictive evidence.

Oncogenic evidence:

Oncogenic: The study discusses the translocation t(12;16)(q13:p11) in malignant myxoid liposarcoma, indicating that it results in a fusion of the CHOP gene with the FUS gene, which contributes to tumor development. This suggests that the variant plays a role in the oncogenic process by creating a fusion protein that may drive tumorigenesis.

Prognostic evidence:

Prognostic: The study demonstrates the prognostic significance of genetic alterations within subtypes of acute lymphoblastic leukemia (ALL), indicating that these alterations correlate with disease outcomes. This suggests that the presence of specific genetic changes can provide insights into the prognosis of patients with different ALL subtypes.

Prognostic evidence:

Prognostic: The study demonstrates the prognostic significance of genetic alterations within subtypes of acute lymphoblastic leukemia (ALL), indicating that these alterations correlate with disease outcomes. This suggests that the presence of specific genetic changes can provide insights into the prognosis of patients with ALL.

Prognostic evidence:

Prognostic: The study demonstrates the prognostic significance of genetic alterations within subtypes of acute lymphoblastic leukemia (ALL), indicating that these alterations correlate with disease outcomes. This suggests that the presence of specific genetic changes can provide insights into the prognosis of patients with ALL.

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Predictive, Oncogenic evidence:

Predictive: The study discusses the efficacy of BI-4732 in overcoming osimertinib resistance mediated by the C797S variant, indicating that this variant correlates with resistance to therapy and highlights the potential for BI-4732 as a treatment option.

Oncogenic: The C797S variant is implicated in osimertinib resistance, suggesting that it contributes to tumor progression and development, as evidenced by the preclinical models used in the study.

Predictive, Oncogenic evidence:

Predictive: The study discusses the resistance to CDK4/6 inhibitors in KRAS-mutant non-small cell lung cancer (NSCLC) and how the inhibition of BRD4 can enhance the efficacy of these inhibitors, indicating a correlation with treatment response. The mention of "synergized with palbociclib to induce senescence" suggests that the variant's presence affects the sensitivity to therapy.

Oncogenic: The abstract indicates that BRD4 overexpression contributes to resistance against CDK4/6 inhibitors in KRAS-mutant NSCLC cells, suggesting that this variant plays a role in tumor progression and development. The context of BRD4's involvement in enhancing cell cycle arrest and promoting senescence further supports its oncogenic role.

Predictive evidence:

Predictive: The abstract mentions that PLX8725 demonstrates promising in vivo activity against PDX models of uLMS harboring GOF alterations in the MAP2K4 gene, indicating a correlation between the variant and response to the therapy. This suggests that the variant may influence treatment sensitivity, warranting further clinical trials.

Predictive, Oncogenic evidence:

Predictive: The study evaluates the response to divarasib, a KRAS G12C inhibitor, in patients with tumors harboring the KRAS G12C mutation, indicating that the variant correlates with treatment response. The mention of "biomarkers of response and resistance" further supports the predictive nature of the evidence regarding therapy outcomes.

Oncogenic: The KRAS G12C mutation is described as a target for the covalent inhibitor divarasib, suggesting that this somatic variant contributes to tumor development or progression. The context of the study focuses on advanced or metastatic solid tumors that harbor this mutation, reinforcing its role in oncogenesis.

Predictive evidence:

Predictive: The study indicates that SRSF2- and U2AF1-mutant leukemias are preferentially sensitive to PARP inhibitors, suggesting a correlation between these mutations and response to therapy. The mention of "PARPi sensitivity" and "PARP1 activity could be predictive of PARPi sensitivity" directly supports the predictive nature of the variant's role in treatment response.