Mutations on Arg282 and Arg248 residues associate with shorter patient survival
[Paragraph-level] PMCID: PMC3973211 Section: RESULTS PassageIndex: 2
Evidence Type(s): Prognostic
Justification: Prognostic: The passage indicates that mutations at Arg282 and Arg248 are associated with shorter patient survival, which correlates with disease outcome independent of therapy.
Gene→Variant (gene-first): 7157:Arg248 7157:Arg282
Genes: 7157
Variants: Arg248 Arg282
Our next goal was to define the molecular signatures of each TSC hamartomatous lesion type using genome-wide DNA methylation and transcript profiling. Unsupervised clustering of DNA methylation array data revealed lesion
[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
Next, we determined whether metformin had superior antitumor activity in KRAS-mutated CRC cell lines to those with KRAS wild type through a cell-viability test. As shown in SI Appendix, Fig. S2A, metformin inhibited the
[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
To analyze the response of KB1(L1363P)P mammary tumors to HRR deficiency-targeted therapy, we performed orthotopic transplantations with spontaneous donor tumors as previously described. To capture the heterogeneity of K
[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
KB1(L1363P)P mammary tumors respond to cisplatin and PARP inhibition
[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
KB1P mammary tumors are mainly adenocarcinomas, defined by their epithelial nature and solid growth pattern (Fig. 3D; Supplementary Fig. S4B). In contrast, KB1(L1363P)P mammary tumors are predominantly carcinosarcomas wi
[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
KB1(L1363P)P mammary tumors show EMT-like phenotypes and limited genomic instability
[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
The embryonic lethality of Brca1LP/LP mice indicates that an intact BRCA1 coiled-coil domain is functionally important in vivo, in line with its requirement for BRCA1-mediated HRR. To analyze whether the functional defec
[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
Brca1 p.L1363P shows a defect in mammary tumor suppression
[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
To verify whether mouse Brca1 p.L1363P phenocopies human BRCA1 p.L1407P, we analyzed Brca1LP/LP;Trp53Delta/Delta (LP/LP) mutant and Brca1LP/+;Trp53Delta/Delta (LP/+) control MEFs for BRCA1-PALB2 interaction and HRR defec
[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
BRCA1 p.L1363P is unable to bind PALB2 and shows hypomorphic activity in HRR
[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
In the complete absence of TP53, Brca1LP/LP mice developed apparently normal until at least E13.5, although no postnatal survival was observed upon compound heterozygous intercrosses (Table 3). This allowed us to isolate
[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
For a first functional analysis of Brca1 p.L1363P in vivo, heterozygous Brca1LP mice were intercrossed and their offspring was genotyped. No Brca1LP/LP mice were born; therefore, embryos were analyzed at different stages
[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
Homozygous Brca1 p.L1363P (FVB) mice die during embryonic development
[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
We used CRISPR/Cas9-mediated genome editing in FVB mouse zygotes to model the BRCA1 coiled-coil domain VUS c.4220T>C p.L1407P, which disrupts the interaction of BRCA1 with PALB2. The BRCA1 coiled-coil domain is well cons
[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
Generation of Brca1 p.L1363P (FVB) mice
[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
MIB-1 labeling indices correlated with the diagnosis and grade assigned prior to H3 K27M IHC testing (Table 1). For the adult cohort, 1 case met WHO criteria for diffuse astrocytoma, WHO grade II (MIB-1 < 1%), 7 cases me
[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
The known lower frequency of ATRX mutation/loss of ATRX nuclear immunostaining in only 10 - 15% of H3 K27M-mutant tumors makes this feature less amenable to comparisons between the 2 cohorts. However, of the 7 adult case
[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
Four cases had other morphologies at initial biopsy, including pure GG (n = 3, pediatric) and PA (n = 1, adult) histologies. One of the GGs was a 16-year-old girl with an original biopsy demonstrating a pure thalamic GG
[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
Table 1 summarizes the ages, gender, anatomical location, initial histological diagnoses, and p53 IHC labeling indices discerned prior to H3 K27M IHC in the 28 H3 K27M-mutant tumors identified in our databases. There wer
[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
Background: H3 K27M mutation was originally described in pediatric diffuse intrinsic pontine gliomas (DIPGs), but has been recently recognized to occur also in adult midline diffuse gliomas, as well as midline tumors wit
[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
To identify somatic mutations in paediatric diffuse intrinsic pontine gliomas (DIPGs), we performed whole genome sequencing of 7 DIPGs and matched germline DNA, and targeted sequencing of an additional 43 DIPGs and 36 no
[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
CDK4/6 inhibition with endocrine therapy is now a standard of care for advanced estrogen receptor positive breast cancer. Mechanisms of CDK4/6 inhibitor resistance have been described pre-clinically, with limited evidenc
[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
Twenty-seven patients with a median age of 49 years (range 23-82) were treated with BRAF inhibitors. Eleven patients received dabrafenib with trametinib, and 16 were treated with vemurafenib. Patients received 150 mg of
[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
Although activating mutations of FGFR3 are frequent in bladder tumors, little information is available on their specific effects in urothelial cells or the basis for the observed mutation spectrum. We investigated the ph
[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
Conclusion: Our findings suggested that the SNPs (rs16879870, rs2641256, rs2761591, rs854936) might play a crucial role in prognosis of HNSCC.
[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
Results: After combining the result of the two stages, 4 SNPs were significantly associated with HNSCC survival (rs16879870 at 6q14.3: adjusted HR = 2.02, 95%CI = 1.50-2.73, P = 3.88 x 10-6; rs2641256 at 17p13.2: adjuste
[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
Mutations in SF3B1 have been identified across several cancer types. This key spliceosome component promotes the efficient mRNA splicing of thousands of genes including those with crucial roles in the cellular response t
[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
Mutations in the KRAS oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (KRASG12D) being the most common. Here, we tested the efficacy of a small-mole
[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
Macrodactyly is a discrete congenital anomaly consisting of enlargement of all tissues localized to the terminal portions of a limb, typically within a 'nerve territory'. The classic terminology for this condition is 'li
[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
Mutations in KRAS and BRAF were associated with inferior PFS and OS of mCRC patients compared with patients with non-mutated tumors. KRAS exon 2 mutation variants were associated with heterogeneous outcome compared with
[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
In 664 tumors, no mutation was detected, 462 tumors were diagnosed with KRAS-, 39 patients with NRAS- and 74 patients with BRAF-mutation. Mutations in KRAS were associated with inferior progression-free survival (PFS) an
[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
In this pooled analysis of metastatic colorectal cancer patients, mutations in KRAS, and BRAF were associated with inferior progression-free and overall survival compared with patients with non-mutated tumors. KRAS exon
[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
PIK3CA encoding the phosphoinositide 3-kinase (PI3K) p110alpha catalytic subunit is frequently mutated in cancer, with mutations occurring widely throughout the primary sequence. The full set of mechanisms underlying how
[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
We also compared HDX-MS differences in full-length p110alpha-p85alpha between WT, H1047R and DeltaC in the presence and absence of pY (Supplementary Fig. 6). The binding of pY led to significant increases for all three c
[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
The H1047R, G1049R, and the DeltaCter constructs showed similar significant increases compared to the WT in the kinase domain (Fig. 5A-C). These included regions covering 850-858 (hinge between the N and C lobes), the ac
[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
HDX-MS experiments were carried out for 4-5 timepoints of exchange (3 s at 1 C, 3, 30, 300, and 3000 s at 20 C) for each complex. The full set of all peptides analysed for both p110alpha and p85alpha are shown in the Sou
[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
To test if C-terminal mutations worked by disrupting the inhibitory interaction with the C-terminus, we carried out HDX-MS studies on six constructs of full-length p110alpha (WT, M1043L, H1047R, G1049R, N1068fs, and a co
[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
For these mutants, we had difficulty in obtaining sufficient yield of the proteins for extensive biophysical analysis. To circumvent this, we used the kinase dead variants to characterise their membrane binding using pro
[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
We characterised the intrinsic ATPase activity of each p110alpha mutant (Fig. 4A + B), and while this assay does not measure biologically relevant PIP3 activity, it can measure intrinsic differences in PI3K activity inde
[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
To understand the regulatory mechanisms underlying the inhibitory interface with the C-terminus we analysed the most frequent oncogenic mutants that occur at or near this interface. While H1047R/L is the most frequent mu
[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
While the disengagement of the ABD and p85 being involved in membrane binding provides a molecular rationale for activation by oncogenic mutations in the ABD, C2, and helical domains, it does not fully explain the molecu
[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
When comparing our data to the full set of missense oncogenic mutations in the ABD, ABD-RBD linker, C2, helical and the N-lobe of the kinase domain we find that all mutations found in >30 tumours except one (E726K) are l
[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
We have extensively characterised the membrane binding of the p110alpha/p85alpha complex using HDX-MS, however, the disengagement of the ABD and p85 from the catalytic core has likely complicated the analysis of membrane
[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
This data comparing the full-length heterodimer vs p110alpha core allowed us to define the effect of ABD removal on the contact site at the ABD-RBD linker. This region still is protected from exchange at early time point
[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
To investigate the role of the ABD domain/p85 regulatory subunit in controlling PI3K enzyme activity, we needed a construct that allowed us to interrogate the dynamic effects of full ABD disengagement. We engineered and
[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
Mutation of several genes, most notably TP53 or ASXL1 transcriptional regulator 1 (ASXL1), were shown to cause a broad pattern of drug resistance. Interestingly, a few drugs trended more sensitive to TP53 mutant cases, s
[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
To examine tumor forming capacity in vivo, we constructed H460 cells that stably express ERBB2 (Fig. 8a) and assessed tumor growth after subcutaneous inoculation of these cells into mice. On the 21st day after transplant
[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
To examine the biologic effects of ERBB2 E401G in cancer cells, we evaluated the proliferative and invasive capacities of H460 cells. We found that cells expressing ERBB2 S310F exhibited a significantly higher proliferat
[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
Biological effects of ERBB2 E401G
[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
Our simulation data showed that the activating mechanisms of ERBB2 E401G and S310F were related to the EGFR-HER2 heterodimer. The dimerization partner appears to be an important determinant of signaling activity. The two
[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
In a previous simulation study, the dimer interfaces of both the EGFR homodimer and the EGFR-HER2 heterodimer were destabilized when the EGFR lost EGF (a specific ligand of EGFR). We therefore conducted MD simulations of
[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
To confirm whether HER2 homodimers or EGFR-HER2 heterodimers are more relevant to the mechanisms of ERBB2 E401G and S310F activation, we analyzed HER-family dimers using microsecond-timescale MD simulations. With regard
[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
HER2 p.(E401G) stabilizes ligand-free EGFR HER2 heterodimer
[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)
C-terminal phosphorylation of HER family proteins is caused by dimerization followed by trans-autophosphorylation, in which one receptor subunit of the dimer phosphorylates the other. Among the HER family proteins, EGFR,
[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
Identification of potential dimerization partners of HER2 E401G protein
[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
Next, we analyzed C-terminal phosphorylation of HER2 using conventional SDS/PAGE and Western blotting. Compared with cells expressing ERBB2 WT, cells expressing ERBB2 S310F (a positive control variant elevating C-termina
[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
First, we examined whether E401G can form disulfide-linked dimers using SDS/PAGE under non-reducing conditions (for preserving disulfide bonds) and Western blotting. Compared with cells expressing ERBB2 WT, H460 cells ex
[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
To examine the functional properties of ERBB2 E401G, an ECD III variant, we evaluated two types of mechanisms of activation of ECD variants previously reported: formation of disulfide-linked dimers and elevation of C-ter
[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
ERBB2 E401G has functional properties similar to those of 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
A 67-year-old Japanese woman, previous healthy, presented with right inguinal pain with no family history of cancer. Fluorodeoxyglucose (FDG)-positron emission tomography with CT showed increased FDG accumulation in the
[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
Detection of ERBB2 E401G VUS in a patient with CUP
[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
After collapsing smMIPs with the same barcode, we achieved > 150-fold coverage for 85% of the protein coding sequences for KRAS, BRAF, HRAS, NRAS, and MAP2K1. Because KRAS codon p.12G and BRAF codon p.600V somatic mutati
[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
EGFR mutation analysis in non-small-cell lung cancer (NSCLC) patients is currently standard-of-care. We determined the uptake of EGFR testing, test results and survival of EGFR-mutant NSCLC patients in the Netherlands, w
[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
HOXC10 is overexpressed in 51% of primary KRAS-mutant tumors (Figure 3A; TCGA, >= 2SD over expression in normal lung), consistent with observations in cell lines (Figure 2B). By analyzing KRAS-mutant tumor/normal matched
[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
This drug combination was also tested on NCI "Rasless" MEFs carrying KRASG12C or KRASG12D mutations. KPT9274 synergized with MRTX849 at all dose combinations yielding suppressed growth of KRASG12C-mutant MEFs (Supplement
[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
KRAS G12C-mutant MIA PaCa-2 (PDAC) and NCI-H358 (NSCLC) cells were exposed to MRTX849/AMG510 and KPT9274 at different dose combinations. As shown in Fig. 2A and B, all three dose combinations tested demonstrated synergis
[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
nan evidence:
Missing abstract
nan
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.
nan
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
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.
nan
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
nan evidence:
Missing abstract
nan
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
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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
nan evidence:
Missing abstract
nan
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.
nan
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
nan evidence:
Missing abstract
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
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
nan evidence:
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nan
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.
nan
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.
nan
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
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
nan evidence:
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nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
nan evidence:
Missing abstract
nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
nan evidence:
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nan
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.
nan
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.
nan
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.
nan
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.
nan
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.
nan
Predictive, Oncogenic evidence:
Predictive: The study discusses the efficacy of the PRMT5 methyltransferase inhibitor MRTX1719 in selectively killing cancers that are codeleted for CDKN2A and MTAP, indicating a correlation between the CDKN2A/MTAP codeletion and response to this specific therapy. This suggests that the presence of the variant is predictive of treatment response in clinical trials for solid tumors.
Oncogenic: The abstract mentions that CDKN2A is the most common homozygously deleted gene in all human cancers, indicating that its deletion contributes to tumor development or progression. This supports the classification of CDKN2A as an oncogenic variant due to its role in cancer biology.
nan
Diagnostic, Oncogenic evidence:
Diagnostic: The study identifies NRG1 fusions as occurring in 0.36% of lung adenocarcinoma cases and discusses their prevalence among specific pathologic subtypes, indicating that these fusions can be used to classify or define a subset of lung cancer.
Oncogenic: The presence of NRG1 fusions, along with other fusions detected in the study, suggests that these alterations contribute to tumor development or progression in lung adenocarcinomas, as they are described in the context of profiling oncogenic drivers.
nan
Predictive evidence:
Predictive: The results indicate that the RET gatekeeper mutations V804L/M/E are specifically mentioned in the context of treatment with RET-specific TKIs, selpercatinib and pralsetinib, which are approved for RET-altered cancers. This suggests that these variants correlate with response to these therapies, highlighting their predictive nature regarding treatment efficacy.
nan
Diagnostic, Oncogenic evidence:
Diagnostic: The study identifies the prevalence of the ERBB2DeltaEx16 variant, including c.1899-880_1946+761del, in Chinese pan-cancer patients, suggesting its role in defining or classifying a disease subtype within this population.
Oncogenic: The presence of the c.1899-880_1946+761del variant among the detected ERBB2DeltaEx16 variants indicates its potential contribution to tumor development or progression, as it is part of a broader category of variants associated with the ERBB2 gene in cancer.
nan
Predictive, Diagnostic evidence:
Predictive: The study reports that the patient carrying the HER2 G292R variant benefited from pyrotinib treatment after progression on prior therapies, indicating a correlation between this variant and a positive response to a specific therapy.
Diagnostic: The mention of the HER2 G292R variant in the context of a metastatic cervical adenocarcinoma patient suggests its role in defining or classifying the disease, particularly as it is associated with activating mutations in HER2 commonly found in this cancer type.
nan
Predictive, Diagnostic evidence:
Predictive: The study demonstrates that the p.L755P mutation correlates with a response to osimertinib treatment in a patient with NSCLC, indicating its potential as a predictive biomarker for therapy response.
Diagnostic: The mention of the p.L755P mutation in the context of defining the patient's cancer subtype (HER2 exon 19 mutation) suggests that this variant is used to classify or confirm the disease.
nan
Predictive, Prognostic evidence:
Predictive: The study assesses the efficacy of pyrotinib in patients with HER2-mutant advanced NSCLC, indicating that the presence of HER2 mutations correlates with response to this specific therapy, as evidenced by the reported objective response rate of 30.0%.
Prognostic: The median overall survival of 14.4 months for patients with HER2-mutant NSCLC suggests that this variant may correlate with disease outcome, independent of therapy, providing prognostic information about the survival of these patients.
nan
Predictive, Prognostic evidence:
Predictive: The study discusses the effectiveness of trastuzumab deruxtecan in patients with HER2-low metastatic breast cancer, indicating that the variant correlates with response to this specific therapy, as evidenced by the significant differences in progression-free survival and overall survival between treatment groups.
Prognostic: The results show that patients with HER2-low metastatic breast cancer had different overall survival rates based on the treatment received, suggesting that the HER2-low status is associated with disease outcomes independent of therapy.
nan
Predictive, Prognostic evidence:
Predictive: The study discusses the effectiveness of trastuzumab deruxtecan in patients with HER2-low metastatic breast cancer, indicating that the variant correlates with response to this specific therapy, as evidenced by the significant improvement in progression-free survival and overall survival compared to the physician's choice of chemotherapy.
Prognostic: The results show that patients with HER2-low metastatic breast cancer had different overall survival rates based on the treatment received, suggesting that the HER2-low status is associated with disease outcomes independent of therapy, as indicated by the reported hazard ratios for death.
nan
Functional evidence:
Functional: The study discusses PAK4, a serine/threonine kinase, and its role in altering molecular functions related to cancer progression, such as controlling cell proliferation and survival. This indicates that the variant affects biochemical pathways and cellular behaviors, which aligns with the functional evidence type.
nan
Predictive, Oncogenic evidence:
Oncogenic: The study discusses the common mutations in FGFR3, specifically mentioning the S249 mutation, and indicates that these mutations contribute to tumor development, as they are described as "somatic activating mutations" that are prevalent in human cancer.
Predictive: The abstract mentions that the study evaluated the sensitivity of various FGFR mutations, including S249, to FGFR tyrosine kinase inhibitors (TKIs), indicating a correlation between the variant and response to therapy.
nan
Predictive, Oncogenic evidence:
Predictive: The study discusses the potential of a combination treatment using DNA hypomethylating agents and PARP inhibitors specifically targeting SETD2-deficient cancers, indicating a correlation with treatment response in these cases. The mention of "synergistically increased cytotoxicity" in SETD2-deficient cell lines supports the predictive nature of the variant's role in therapy response.
Oncogenic: The abstract highlights that SETD2 deficiency plays a significant role in aggressive forms of cancer, particularly in clear cell renal cell carcinomas, suggesting that this somatic variant contributes to tumor development and progression. The context of "SETD2 deficiency alters the epigenetic landscape" further supports its oncogenic classification.
nan
Predictive, Oncogenic evidence:
Predictive: The study discusses the KRASG12D mutation in the context of therapy, specifically mentioning the response to the MRTX1133 inhibitor and its effects on pancreatic adenocarcinoma (PDAC). The results indicate that MRTX1133 leads to regression of advanced PDAC and highlights the importance of CD8+ T cells and immune checkpoint blockade in enhancing treatment efficacy, which aligns with predictive evidence regarding therapy response.
Oncogenic: The KRASG12D mutation is described as being present in nearly half of pancreatic adenocarcinomas and is implicated in tumor development and progression, as evidenced by the use of various models of KRASG12D-driven PDAC. The study demonstrates that inhibiting this mutation leads to significant changes in tumor growth and microenvironment, supporting its role as an oncogenic driver.
nan
Predictive, Oncogenic evidence:
Predictive: The study discusses how FGFR2 fusions are associated with moderate response rates to FGFR inhibitors and highlights the emergence of resistance due to secondary mutations, indicating a correlation between the FGFR2 variant and treatment response. The findings suggest that combining FGFR and EGFR inhibitors could enhance therapeutic efficacy, further supporting the predictive nature of the FGFR2 variant in treatment contexts.
Oncogenic: The abstract mentions that FGFR2 fusions are present in cholangiocarcinoma and that these fusions contribute to tumor development and progression, as evidenced by the therapeutic studies conducted on patient-derived models. This indicates that the FGFR2 variant plays a role in oncogenesis within this cancer type.
nan
Predictive, Diagnostic evidence:
Predictive: The study discusses the clinical activity of pralsetinib, a selective RET inhibitor, in patients with RET fusion-positive NSCLC, indicating a correlation between the presence of the RET fusion and the response to this specific therapy. The overall response rates reported for treatment-naive patients and those with prior chemotherapy further support this predictive evidence.
Diagnostic: The presence of RET fusions is highlighted as a defining characteristic in the context of non-small-cell lung cancer (NSCLC), suggesting that these variants are used to classify patients with this disease subtype. The mention of RET fusion-positive NSCLC indicates its role as a biomarker for diagnosis.
nan
Functional evidence:
Functional: The variant D9E is mentioned in the context of pAKT-S473, indicating that it is associated with the phosphorylation state of AKT, which suggests that it alters molecular function related to signaling pathways in breast cancer cells. This aligns with the definition of functional evidence as it focuses on the biochemical activity of the protein.
nan
Predictive, Oncogenic evidence:
Predictive: The study discusses how specific FGFR3 mutations, including N540K, result in distinct changes in drug efficacy when treated with various inhibitors, indicating a correlation between the variant and response to therapy.
Oncogenic: The abstract mentions that certain mutations in FGFRs, including N540K, are implicated as drivers in diverse tumors, suggesting their role in tumor development or progression.
nan
Predictive, Diagnostic evidence:
Diagnostic: The study discusses the presence of the R678Q mutation in various breast cancer subtypes, indicating its association with specific histological types such as invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC). This suggests that the variant can be used to classify or define the disease based on tumor type.
Predictive: The abstract mentions that patients carrying the R678Q mutation seem to be good candidates for anti-HER2 therapy, as they show favorable outcomes and a good response to current pharmacological treatments. This indicates a correlation between the variant and the response to therapy, classifying it as predictive evidence.
nan
Oncogenic evidence:
Oncogenic: The introduction of the ERBB2 mutation S310F into human pancreatic epithelial cells causes oncogenic transformation, increasing ERBB2 signaling and promoting tumor growth, indicating that it contributes to tumor development.
nan
Oncogenic evidence:
Oncogenic: The abstract discusses the KRAS protein as a common driver in human cancer, indicating that mutations in KRAS, including those at the Q61 position, contribute to tumor development and progression. The results section further emphasizes the oncogenic nature of KRAS mutations, particularly highlighting their prevalence in various cancers.
nan
nan evidence:
There are no mentions of the variant in the abstract or results section provided. Therefore, no CIViC evidence types can be classified based on the information given.
nan
Predictive, Oncogenic evidence:
Predictive: The study indicates that the ALK Arg1275Gln mutation is the only mutation predicted to be sensitive to ALK inhibition with crizotinib, suggesting a correlation between this variant and response to therapy.
Oncogenic: The presence of the somatic ALK Arg1275Gln mutation is described as the most common ALK hotspot mutation observed in neuroblastoma, indicating its role in tumor development or progression.
nan
Predictive, Diagnostic evidence:
Predictive: The study discusses the response of patients with KRAS G12D-mutant NSCLC to bortezomib, indicating that exceptional responses can be achieved, which correlates with treatment sensitivity. The mention of "KRAS G12D mutation alone, however, is not a robust predictor of response" suggests a nuanced relationship between the variant and therapy response.
Diagnostic: The abstract states that patients with advanced KRAS G12D-mutant NSCLC were eligible for the trial, indicating that the presence of this variant is used to classify and define a specific subtype of lung cancer. This aligns with the use of the variant as a biomarker for patient selection in clinical trials.
nan
Oncogenic, Functional evidence:
Functional: The study discusses the variant E401G in the context of its location in the extracellular domain of the ERBB2 gene, indicating that functional analyses of such variants have been limited, which suggests an exploration of how this variant may alter molecular function.
Oncogenic: The mention of ERBB2 gene alterations, including the E401G variant, as promising target alterations in cancer treatment implies that this variant may contribute to tumor development or progression, aligning with oncogenic behavior.
nan
Predictive, Functional evidence:
Predictive: The study indicates that patients with the S310F mutation responded to trastuzumab with or without the pertuzumab combination, suggesting a correlation between the variant and treatment response. This aligns with the predictive evidence type as it discusses the variant's impact on therapy effectiveness.
Functional: The research demonstrates that the S310F mutant HER2 can form an active heterodimer with EGFR, which is a functional alteration in molecular interactions. This evidence supports the functional type as it focuses on the biochemical behavior of the variant in relation to receptor activation and dimerization.
nan
Predictive, Oncogenic evidence:
Predictive: The study discusses the emergence of the ESR1 Y537S mutation in the context of resistance to CDK4/6 inhibitors, indicating that this variant may correlate with treatment resistance, which is a key aspect of predictive evidence.
Oncogenic: The emergence of the ESR1 Y537S mutation is implicated in the development of resistance mechanisms during treatment, suggesting that this somatic variant contributes to tumor progression in the context of advanced breast cancer.
nan
Functional evidence:
Functional: The study discusses the effects of various treatments on the expression of cyclin E and the levels of phosphorylated histone variant H2AX (gammaH2AX), indicating that the variant E in 72 alters molecular function related to DNA damage response and cell cycle regulation. This is supported by the immunoblotting results showing changes in protein expression levels in response to treatment.
nan
Predictive, Oncogenic evidence:
Predictive: The study indicates that HP breast cancers with the HER2V777L mutation show resistance to the pan-HER tyrosine kinase inhibitor, neratinib, but respond effectively to the combination of neratinib and trastuzumab deruxtecan, demonstrating a correlation between the variant and treatment response.
Oncogenic: The presence of the HER2V777L mutation is associated with accelerated tumor formation and increased invasion and migration in breast cancer models, indicating that this somatic variant contributes to tumor development and progression.
nan
Diagnostic, Functional evidence:
Functional: The study discusses the functional analysis of RAD51C variants, including p.Leu262Val (L262V), indicating that this variant was predicted to cause aberrant splicing based on the Splice AI algorithm. This suggests that the variant alters molecular function, specifically splicing activity.
Diagnostic: The abstract mentions that the analysis provides information for the classification of the cancer relevance of RAD51C variants, implying that variants like p.Leu262Val (L262V) are used to define or classify disease relevance, which aligns with diagnostic evidence.
nan
Diagnostic, Oncogenic evidence:
Diagnostic: The study describes the GAB1::ABL1 fusion as a distinct entity in soft tissue tumors, indicating its role in defining and classifying these tumors. The mention of various tumor types harboring this fusion supports its use as a biomarker for diagnosis.
Oncogenic: The presence of the GAB1::ABL1 fusion in the tumors suggests that it contributes to tumor development or progression, as the study focuses on tumors characterized by this specific genetic alteration. The characterization of these tumors as a distinct entity further implies a role in oncogenesis.
nan
Predictive, Oncogenic evidence:
Oncogenic: The abstract states that canonical mutations in the PIK3CA gene promote oncogenesis via specific signaling pathways, indicating that these somatic variants contribute to tumor development.
Predictive: The abstract mentions that these mutations may serve as predictive biomarkers of response to PI3K inhibitors and NSAID therapy, suggesting a correlation with treatment response.
nan
Oncogenic, Functional evidence:
Oncogenic: The study describes how PIK3CA mutations were assessed for their activity in promoting tumor growth and transformation, indicating that these somatic variants contribute to tumor development or progression.
Functional: The research highlights that specific PIK3CA variants exhibit variant-specific activation of PI3K signaling and other pathways, demonstrating that these mutations alter molecular function, which was assessed through in vitro and in vivo assays.
nan
Oncogenic, Functional evidence:
Oncogenic: The study describes how PIK3CA mutations were assessed for their activity in promoting tumor growth and transformation, indicating that these somatic variants contribute to tumor development or progression.
Functional: The research highlights that specific PIK3CA variants exhibit variant-specific activation of PI3K signaling and other pathways, demonstrating that these mutations alter molecular function, which was assessed through in vitro and in vivo assays.
nan
Predictive, Functional evidence:
Functional: The study evaluated the transforming activities of the G776V mutation, indicating that it is an activating mutation. This suggests that the variant alters molecular function, which is a key aspect of the functional evidence type.
Predictive: The abstract discusses the varying sensitivities of ERBB2 mutations, including G776V, to ERBB2-targeted inhibitors like afatinib and neratinib. This indicates a correlation between the variant and response to specific therapies, which aligns with the predictive evidence type.
nan
nan evidence:
Missing abstract
nan
Diagnostic, Oncogenic evidence:
Diagnostic: The study discusses the diagnostic yield of PIK3CA sequencing in patients with PIK3CA-related overgrowth spectrum (PROS), indicating that the variant is used to define and confirm the disease, as evidenced by the identification of disease-causing mutations in 66.7% of patients. The results also highlight the importance of specific tissue samples for optimal diagnosis, further supporting its role as a diagnostic marker.
Oncogenic: The abstract mentions the identification of strong oncogenic mutations in patients with PIK3CA-related overgrowth spectrum, suggesting that these somatic variants contribute to tumor development or progression. The differential frequency of these mutations in patients with and without brain overgrowth further supports their oncogenic potential.
nan
Oncogenic evidence:
Oncogenic: The study discusses how different oncogenic mutations in the PIK3CA gene, including G1049R, contribute to increased activity, indicating that this variant plays a role in tumor development or progression. The mention of G1049R in the context of oncogenic mutations supports its classification as an oncogenic variant.
nan
nan evidence:
Missing abstract
nan
Oncogenic, Functional evidence:
Oncogenic: The study discusses how the lysine-to-methionine mutation (H3K27M) in histone H3 contributes to the development of diffuse midline gliomas (DMGs), indicating its role in tumor progression and the associated lethality of these cancers.
Functional: The variant is shown to alter histone modifications, specifically leading to a global reduction in the repressive H3K27me3 mark and an increase in H3K27ac, which suggests that the mutation affects molecular functions related to chromatin remodeling and gene expression regulation.
nan
nan evidence:
There are no mentions of the variant in the abstract or results section provided. Therefore, no CIViC evidence types can be classified based on the information given.
nan
Predictive, Prognostic evidence:
Predictive: The study identifies the lncRNA NEAT1 as commonly upregulated in melanoma patients with complete therapeutic response and GBM patients with longer survival following anti-PD-1/PD-L1 treatment, suggesting a correlation between NEAT1 expression and response to this immunotherapy.
Prognostic: The results indicate that NEAT1 expression is associated with longer survival in GBM patients, which correlates with disease outcome independent of therapy, thus providing prognostic information.
nan
Predictive, Diagnostic, Oncogenic evidence:
Predictive: The study discusses the correlation between BRCA1/2 mutations and the response to olaparib therapy, indicating that the antitumor activity of olaparib is associated with platinum sensitivity, which is a key aspect of predictive evidence regarding treatment response.
Diagnostic: The abstract mentions that patients with BRCA1/2 mutations were treated, indicating that these mutations are used to classify and confirm the presence of a specific subtype of ovarian cancer, thus providing diagnostic evidence.
Oncogenic: The presence of BRCA1/2 mutations is linked to defective homologous recombination DNA repair, which contributes to tumor development in ovarian cancer, supporting the classification of these variants as oncogenic.
nan
nan evidence:
Missing abstract
nan
Diagnostic, Oncogenic evidence:
Diagnostic: The study identifies the ETV6-NTRK3 fusion gene as a specific genetic alteration in secretory breast carcinoma (SBC), indicating its role in defining and confirming this subtype of breast cancer. The presence of the fusion gene was assessed using FISH assays, which further supports its use as a diagnostic marker for SBC.
Oncogenic: The abstract mentions that the biological consequence of the ETV6-NTRK3 translocation is the expression of a chimeric protein tyrosine kinase with potent transforming activity, suggesting that this somatic variant contributes to tumor development or progression in SBC.
nan
Diagnostic, Oncogenic evidence:
Diagnostic: The study discusses the distinct molecular variants of medulloblastoma, indicating that certain somatic copy number aberrations (SCNAs) are predominantly subgroup-enriched, which suggests their role in classifying the disease into specific subtypes.
Oncogenic: The identification of recurrent translocations and somatic copy number aberrations, such as PVT1-MYC and PVT1-NDRG1, indicates that these variants contribute to tumor development and progression in specific groups of medulloblastoma.
nan
Predictive, Diagnostic evidence:
Predictive: The study indicates that ALK mutations may serve as a biomarker of response to lorlatinib, particularly in patients who have failed one or more second-generation ALK TKIs, suggesting a correlation between the presence of these mutations and treatment efficacy. The objective response rate was significantly higher in patients with ALK mutations compared to those without, demonstrating the predictive value of these mutations for treatment response.
Diagnostic: The study discusses the detection of ALK mutations in patients with ALK-positive non-small-cell lung cancer, indicating that these mutations can be identified through plasma and tissue genotyping. This suggests that ALK mutation status can be used to classify patients and potentially guide treatment decisions, fulfilling the criteria for diagnostic evidence.
nan
Predictive, Diagnostic evidence:
Predictive: The abstract discusses the addition of selpercatinib to osimertinib for patients with EGFR-mutant NSCLC and acquired RET fusion as a mechanism of resistance, indicating a correlation with treatment response and clinical benefit.
Diagnostic: The results section specifies that a pathologic diagnosis of lung cancer and the presence of a RET fusion detected at or after the onset of resistance to osimertinib therapy were required, indicating that the RET fusion is used to classify or confirm the disease state.
nan
Oncogenic evidence:
Oncogenic: The variant c.1976delG in the RNF43 gene is mentioned in the context of comprehensive genomic profiling, which is used to identify alterations that may contribute to tumor development or progression. The study highlights the detection of this variant alongside other genomic alterations, suggesting its potential role in the cancer's molecular landscape.
nan
Diagnostic evidence:
Diagnostic: The study discusses the classification and characterization of ATRT subgroups, indicating that the variant is used to define and classify disease subtypes, which aligns with the criteria for diagnostic evidence.
nan
nan evidence:
Based on the provided abstract and results section, there is no specific information regarding the variant(s) mentioned in the study. Therefore, I cannot classify any evidence types as there are no relevant statements to support any of the CIViC evidence types.
nan
Predictive, Diagnostic evidence:
Diagnostic: The study mentions that 5.2% of patients had a change in diagnosis, indicating that the identified variants are used to classify or define disease subtypes. Additionally, the mention of pathogenic cancer-predisposing variants in 16.2% of patients supports the use of these variants in confirming or excluding specific diseases.
Predictive: The abstract states that 71.4% of patients had therapeutic targets, and 31% of those evaluated showed objective evidence of clinical benefit, suggesting that the identified variants correlate with response to specific therapies. This indicates a predictive relationship between the variants and treatment outcomes.
nan
Predictive, Functional evidence:
Functional: The study employs biochemical and cell-based transcriptional assays to evaluate the structural and functional defects of 117 distinct BRCA1 missense variants, indicating that these variants alter molecular function, such as protein folding stability and transcriptional activation capability.
Predictive: The authors correlate the assay results with family history and clinical data to predict disease risk associated with each variant, suggesting that the functional effects of the variants can inform on their potential clinical significance and associated cancer risk.
nan
Predictive, Oncogenic evidence:
Predictive: The study discusses the efficacy of combination therapies involving inhibitors targeting the KRAS G12C-mutant protein, indicating a correlation with treatment response in colorectal cancer patients. The mention of exploring effective combination drugs for patients with KRAS G12C mutations suggests a predictive relationship between the variant and therapeutic outcomes.
Oncogenic: The KRAS G12C mutation is implicated in the growth of colorectal cancer cells, as evidenced by the use of patient-derived colorectal cancer stem cell spheroids to demonstrate the impact of this somatic variant on tumor growth. This indicates that the G12C variant contributes to tumor development or progression in this context.
nan
Predictive, Oncogenic evidence:
Oncogenic: The study identifies the HMGA2-EGFR fusion gene as having transforming potential and a high tumor-forming capacity in cell culture and in vivo, indicating that this somatic variant contributes to tumor development and progression in glioblastoma.
Predictive: The findings suggest that the EGFR kinase inhibitor erlotinib blocked sphere formation of TGS-01 cells and inhibited tumor formation in vivo, indicating that the HMGA2-EGFR fusion gene may correlate with sensitivity to this specific therapy.
nan
Predictive, Diagnostic evidence:
Diagnostic: The study mentions that eligible patients had "centrally confirmed EGFR mutation (exon 19 deletion [Ex19del]/L858R)," indicating that the presence of the L858R variant is used to classify and confirm the diagnosis of NSCLC.
Predictive: The abstract discusses the "efficacy of adjuvant osimertinib in resected EGFR-mutated NSCLC," suggesting that the presence of the L858R variant correlates with response to the therapy, which is osimertinib.
nan
Predictive, Diagnostic, Oncogenic evidence:
Predictive: The study discusses the response to a combination of BRAF and EGFR inhibitors in patients with BRAF V600E positive metastatic colorectal cancer, indicating that the variant correlates with treatment response.
Diagnostic: The mention of "BRAF V600E Positive" in the context of the trial suggests that this variant is used to classify patients for the study, confirming its role as a biomarker for identifying a specific subtype of cancer.
Oncogenic: The reference to BRAF V600E in the context of metastatic colorectal cancer implies that this somatic variant contributes to tumor development or progression, as it is associated with a specific cancer type.
nan
Predictive, Diagnostic evidence:
Predictive: The study discusses the potential implications of MET genomic amplification and protein expression on the efficacy of crizotinib, indicating that these factors may influence treatment response in neuroblastoma. This aligns with the predictive evidence type as it relates to therapy and treatment response.
Diagnostic: The characterization of MET genomic and protein expression status in neuroblastoma samples suggests that these variants can be used to define or classify the disease, particularly in the context of their low prevalence in the cohort studied. This supports the diagnostic evidence type as it relates to disease association.
nan
Oncogenic evidence:
Oncogenic: The study identifies a splice site mutation in the c-Met gene that is associated with gastric cancer cell lines, indicating that this somatic variant contributes to tumor development or progression. The findings suggest that the mutation leads to a functional alteration that promotes oncogenic behavior, particularly in the context of c-Met amplification.
nan
nan evidence:
Missing abstract