Predictive, Prognostic evidence:

Predictive: The study discusses the treatment of patients with BRAFV600-mutant melanoma using sequential immunotherapy and BRAF/MEK inhibition, indicating that the BRAFV600 mutation correlates with response to these therapies, as evidenced by the overall survival rates reported in the results.

Prognostic: The abstract mentions overall survival (OS) as a primary endpoint, with specific survival rates reported for different treatment arms, indicating that the BRAFV600 mutation has prognostic implications for patient outcomes in terms of survival.

Predictive, Prognostic evidence:

Prognostic: The study reports that patients with RB1 wild-type (WT) had a median overall survival (OS) of 23.1 months compared to 5 months for RB1 mutant patients, indicating that the RB1 variant correlates with disease outcome independent of therapy.

Predictive: The results indicate that RB1 WT patients had significantly improved outcomes with nivolumab therapy compared to those with RB1 mutations, suggesting that the RB1 variant is predictive of response to this specific treatment.

Diagnostic, Functional evidence:

Diagnostic: The study discusses the identification of genomic features, including gene fusions and IKZF1 deletions, which are used to refine risk stratification in acute lymphoblastic leukemia (ALL). This indicates that the variants are being utilized to classify and define the disease, supporting their role as diagnostic markers.

Functional: The study mentions the development of an approach to detect IKZF1 deletions from RNA-seq data, which implies that the variant alters molecular function and can be validated through assays. This suggests a functional aspect of the variant in relation to its detection and significance in ALL.

Prognostic, Oncogenic, Functional evidence:

Oncogenic: The study identifies YES1 as a novel targetable oncogene driving SCLC maintenance and metastasis, indicating that it contributes to tumor development and progression. The results show that genetic depletion of YES1 dramatically reduced tumor growth and metastasis, further supporting its role as an oncogenic driver.

Prognostic: YES1 overexpression or gain/amplification was found to be an independent predictor of poor prognosis in SCLC clinical samples, suggesting that it correlates with disease outcome independent of therapy.

Functional: The study describes how YES1-inhibited cells revealed alterations in the replisome and DNA repair processes, indicating that the variant alters molecular function, which is supported by in vitro functional experiments.

Diagnostic evidence:

Diagnostic: The study identifies four new CNS tumor entities associated with recurrent genetic alterations, which facilitates diagnosis and appropriate therapy for patients with these tumors. This indicates that the variants are used to classify and define specific disease subtypes, supporting their role as diagnostic markers.

Oncogenic, Functional evidence:

Functional: The study demonstrates that the somatic mutation c.349A > G (p.R117G) results in modestly reduced CHEK2 kinase activity compared to wild-type CHEK2, indicating that this variant alters the molecular function of the CHEK2 protein. This is supported by the investigation of the functions of the mutants in vivo, which highlights the impact of the mutation on protein activity.

Oncogenic: The identification of the somatic mutation c.349A > G (p.R117G) in prostate tumor specimens suggests that this variant may contribute to tumor development or progression, as it is associated with reduced CHEK2 activation in response to DNA damage and/or oncogenic stress. This aligns with the role of CHEK2 as a tumor suppressor, further supporting its oncogenic potential in the context of prostate cancer.

Diagnostic, Oncogenic evidence:

Diagnostic: The study discusses how patients with VHL disease inherit a mutation in one VHL allele, which allows for the examination of heterozygous VHL expression in neutrophils. This indicates that the variant is used to define and study the effects of VHL mutations in the context of a specific disease, thus supporting its classification as diagnostic.

Oncogenic: The mention of heterozygous VHL defects perturbing normal responses suggests that the variant contributes to tumor development or progression, particularly in the context of VHL disease. This aligns with the oncogenic classification as it implies a role in cancer biology.

Predictive, Oncogenic evidence:

Predictive: The study indicates that the growth of imatinib-resistant cell lines in response to sequential treatment with dasatinib and nilotinib was associated with the T315I variant, suggesting that this variant correlates with resistance to these therapies.

Oncogenic: The presence of T315I in the context of imatinib-resistant chronic myelocytic leukemia (CML) implies that this somatic variant contributes to tumor progression and resistance mechanisms, as it is associated with the growth of resistant cell lines.

Predictive, Oncogenic evidence:

Predictive: The study discusses the limited response of colon cancer patients harboring the BRAF(V600E) variant to the drug PLX4032 (vemurafenib), indicating a correlation between the variant and resistance to this specific therapy.

Oncogenic: The BRAF(V600E) variant is described as an "oncogenic lesion," suggesting that it contributes to tumor development or progression, particularly in the context of colon cancer.

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Predictive, Oncogenic evidence:

Predictive: The study mentions that the patient with a MAP3K8 fusion was treated with a MEK inhibitor and experienced a transient clinical response, indicating a correlation between the variant and sensitivity to therapy.

Oncogenic: The abstract states that MAP3K8 rearrangements are the most common genetic event in spitzoid melanoma, suggesting that this somatic variant contributes to tumor development or progression.

Predictive, Prognostic evidence:

Predictive: The study evaluates the efficacy of darolutamide in delaying metastasis and death in men with nonmetastatic, castration-resistant prostate cancer, indicating a correlation with treatment response. The results show a significant improvement in metastasis-free survival with darolutamide compared to placebo, which supports its predictive value in therapy response.

Prognostic: The median metastasis-free survival was reported as significantly longer with darolutamide (40.4 months) compared to placebo (18.4 months), indicating that the variant (in this case, the treatment with darolutamide) correlates with improved disease outcome independent of therapy. This suggests a prognostic role in terms of survival outcomes for patients receiving this treatment.

Functional evidence:

Functional: The study describes the development of a cDNA-based functional assay to classify BRCA1 variants of uncertain significance (VUSs) based on their ability to functionally complement BRCA1-deficient mouse embryonic stem cells, indicating that the variants alter molecular function.

Diagnostic, Oncogenic evidence:

Diagnostic: The study discusses the genomic landscapes of various neoplastic cyst types, including serous cystadenomas (SCAs), intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms (MCNs), indicating their capacity to progress to cancer. This classification of cyst types based on their genetic mutations and potential for malignancy supports the use of these variants in defining and confirming disease subtypes.

Oncogenic: The identification of inactivating mutations in RNF43 as a suppressor of IPMNs and MCNs suggests that these somatic mutations contribute to tumor development and progression. Additionally, the presence of mutations in CTNNB1 in solid pseudopapillary neoplasms (SPNs) further supports the oncogenic role of these variants in the context of tumorigenesis.

Predictive, Oncogenic evidence:

Oncogenic: The study identifies a novel gene rearrangement involving RASGRF1 that contributes to cellular transformation and promotes in vivo tumorigenesis, indicating its role in tumor development.

Predictive: The findings suggest that cells driven by RASGRF1 fusions are sensitive to targeting of the RAF-MEK-ERK pathway, which correlates with potential therapeutic strategies for tumors harboring these alterations.

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Predictive, Oncogenic evidence:

Predictive: The study discusses how EGFR-D770>GY and variants with G770 equivalence show sensitivity to specific EGFR-TKIs, indicating a correlation with response to therapy. The mention of clinical benefits and radiographic responses to afatinib, dacomitinib, and other TKIs further supports this classification.

Oncogenic: The variants are described in the context of their role in tumor development, particularly as they are part of EGFR exon 20 insertion mutations that are implicated in lung cancer. The study's focus on these mutations and their effects on cellular behavior in preclinical models suggests their contribution to oncogenesis.

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Oncogenic, Functional evidence:

Oncogenic: The variant G168E is mentioned in the context of RUNX1 mutations, which are implicated in the M2 subtype of acute myeloid leukemia (AML) and are associated with tumor development and progression. This suggests that the G168E variant contributes to oncogenic processes in this context.

Functional: The G168E variant is described as a missense mutation within the RUNT domain of RUNX1, which is known to affect the protein's function as a transcription factor. This indicates that the variant alters the molecular or biochemical function of RUNX1, impacting its role in gene regulation.

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Diagnostic, Oncogenic evidence:

Diagnostic: The abstract states that the H3 K27M mutation may have diagnostic implications as it is a hallmark of diffuse midline gliomas, indicating its role in classifying or confirming a specific disease subtype.

Oncogenic: The mention of the H3F3A K27M mutation in the context of a sonic hedgehog medulloblastoma suggests that this somatic variant contributes to tumor development or progression, aligning with the definition of oncogenic evidence.

Predictive, Prognostic evidence:

Predictive: The study discusses the correlation between the H3.3K27M mutation and the response to an H3.3K27M-targeted peptide vaccine, indicating that patients with H3.3K27M-specific CD8+ T cell responses demonstrated prolonged overall survival compared to nonresponders. This suggests that the variant is predictive of treatment response in the context of the vaccine therapy.

Prognostic: The results indicate that the median overall survival (OS) was significantly longer for patients with an expansion of H3.3K27M-reactive CD8+ T cells compared to those without, highlighting the variant's role in correlating with disease outcome independent of therapy.

Predictive, Functional evidence:

Functional: The study discusses how the variant p.L1143P impairs PALB2 function, specifically in the context of homologous recombination (HR) and its interaction with BRCA1, indicating that this variant alters the molecular function of the PALB2 protein. The results section highlights that p.L1143P was identified as a variant that negatively impacts PALB2's role in DNA repair, demonstrating its functional consequences.

Predictive: The abstract mentions that the results from functional assays can be valuable for predicting cancer risk and responsiveness to cancer therapy, specifically referencing treatments like PARP inhibitors and platinum-based chemotherapy. This suggests that the variant p.L1143P may correlate with treatment response, indicating its predictive value in a therapeutic context.

Diagnostic, Oncogenic evidence:

Diagnostic: The study mentions that the trial involves patients with diffuse midline gliomas characterized by a K27M mutation in genes encoding histone H3, indicating that this variant is used to classify and define a specific subtype of the disease.

Oncogenic: The presence of the K27M mutation in histone H3 is associated with tumor development in diffuse midline gliomas, suggesting that this somatic variant contributes to the progression of the disease.

Predictive, Prognostic, Predisposing evidence:

Predisposing: The study discusses germline mutations in DNA damage repair (DDR) genes, specifically mentioning that these mutations are identified in a significant proportion of patients with metastatic prostate cancer, indicating an inherited risk for developing the disease.

Prognostic: The results indicate that germline BRCA2 mutations are associated with a significant impact on cause-specific survival (CSS) in metastatic castration-resistant prostate cancer (mCRPC), demonstrating that these mutations correlate with disease outcome independent of therapy.

Predictive: The study highlights significant interactions between germline BRCA2 status and treatment type, suggesting that the presence of g BRCA2 mutations may influence the response to specific therapies, such as androgen signaling inhibitors versus taxane therapy.

Prognostic, Predisposing evidence:

Predisposing: The study discusses germline mutations in BRCA1/2 and ATM as being associated with prostate cancer risk, indicating that these inherited mutations confer an increased likelihood of developing lethal prostate cancer.

Prognostic: The results indicate that mutation carriers of BRCA1/2 and ATM are independent predictors of lethal prostate cancer, correlating with earlier age at death and shorter survival time, which reflects the prognostic significance of these variants in disease outcome.

Diagnostic, Prognostic evidence:

Prognostic: The study indicates that prostate cancer (PCa) with germline BRCA1/2 mutations is associated with poorer survival outcomes, as evidenced by the significantly shorter cause-specific survival (CSS) in carriers compared to noncarriers (8.6 years vs. 15.7 years, P = .015). This suggests that the presence of these mutations correlates with disease outcome independent of therapy.

Diagnostic: The abstract discusses the association of BRCA1/2 mutations with specific clinicopathologic characteristics of prostate tumors, such as higher Gleason scores and increased nodal involvement, indicating that these mutations can be used to classify and define the disease phenotype in prostate cancer.

Prognostic, Oncogenic evidence:

Prognostic: The abstract states that "HOXC10 upregulation was associated with short overall survival," indicating that the variant correlates with disease outcome independent of therapy. This suggests that higher levels of HOXC10 expression may predict poorer survival in glioma patients.

Oncogenic: The findings indicate that "HOXC10 knock-down inhibited cell proliferation, colony formation, migration and invasion," which demonstrates that HOXC10 contributes to tumor development and progression in glioma. This supports the classification of HOXC10 as an oncogenic variant due to its role in promoting aggressive tumor behavior.

Oncogenic evidence:

Oncogenic: The variant D33E is described as displaying tumorigenicity and constitutive activation of known RAS effector pathways, indicating that it contributes to tumor development or progression. This aligns with the evidence type that focuses on somatic variants driving cancer behavior.

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Predictive, Oncogenic evidence:

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.

Oncogenic: The K700E variant is described as a prevalent cancer-associated mutation that contributes to a BRCA-like cellular phenotype, suggesting its role in tumor development and progression.

Diagnostic, Functional evidence:

Functional: The study describes an assay that measures the effects of variants in MLH1 and MSH2 on the function of the gene products, specifically their ability to undergo cell death following exposure to a methylating agent. This indicates that the variants alter the molecular function related to DNA mismatch repair.

Diagnostic: The research focuses on identifying variants of unknown significance (VUS) in MLH1 and MSH2 that can help classify patients with suspected Lynch syndrome, thus linking the variants to disease classification and diagnosis.

Diagnostic, Functional evidence:

Functional: The study describes an assay that measures the effects of variants in MLH1 and MSH2 on the function of the gene products, specifically their ability to undergo cell death following exposure to a methylating agent. This indicates that the variants alter the molecular function related to DNA mismatch repair.

Diagnostic: The research focuses on identifying variants of unknown significance (VUS) in MLH1 and MSH2 that can help classify patients with suspected Lynch syndrome, thereby linking the presence of these variants to a specific disease context.

Functional evidence:

Functional: The study utilized a validated functional assay of BRCA2 homologous recombination (HR) DNA-repair activity to assess the impact of variants of uncertain significance (VUS) on the molecular function of BRCA2, indicating that these variants alter biochemical activity related to DNA repair. This is supported by the comprehensive evaluation of 139 variants, where functional assay results were integral to determining pathogenicity.

Functional evidence:

Functional: The study discusses the variant c.5044G>A in the context of testing BRCA1 mRNA levels, indicating that the variant may alter molecular function, which is a key aspect of functional evidence. The mention of "intermediate function scores" suggests that the variant's impact on BRCA1 activity is being assessed, aligning with the definition of functional evidence.

Diagnostic, Oncogenic evidence:

Diagnostic: The study discusses the PALB2 c.2514+1G>C variant in the context of its association with homologous recombination deficiency, suggesting its role in defining or classifying a specific disease context, particularly in pancreatic adenocarcinoma.

Oncogenic: The variant c.2514+1G>C is identified as a somatic mutation in the results section, indicating its contribution to tumor development or progression, particularly in the context of pancreatic adenocarcinoma.

Predictive, Diagnostic evidence:

Predictive: The study indicates that the GALNT14-rs9679162 "TT" genotype is associated with favorable clinical outcomes in hepatocellular carcinoma (HCC) treated by transarterial chemoembolization (TACE), suggesting a correlation with treatment response. Additionally, the results show that patients with the "non-TT" genotype who received a combination of TACE and sorafenib had improved outcomes compared to those who only received TACE, further supporting the predictive nature of the variant in treatment efficacy.

Diagnostic: The abstract mentions that patients were genotyped for GALNT14-rs9679162 before TACE, indicating that this variant is used to classify patients into "TT" and "non-TT" genotypes. This classification is essential for determining treatment strategies, thus supporting its role as a diagnostic marker in the context of HCC.

Predictive, Oncogenic evidence:

Predictive: The study discusses how treatment with the KRAS(G12C) inhibitor AMG 510 led to regression of KRASG12C tumors and improved anti-tumor efficacy, indicating a correlation with response to therapy.

Oncogenic: The abstract highlights that KRAS is a frequently mutated oncogene and specifically mentions the KRAS(G12C) variant's role in tumor development, suggesting its contribution to tumor progression.

Predictive, Oncogenic evidence:

Predictive: The study indicates that the FLT3 K663Q mutation was potently inhibited by Sunitinib, demonstrating a correlation with treatment response, as Sunitinib reduced proliferation and induced apoptosis in cells expressing this variant.

Oncogenic: The abstract describes FLT3 K663Q as a novel gain-of-function mutation associated with acute myeloid leukemia (AML), suggesting that it contributes to tumor development or progression.

Predictive evidence:

Predictive: The study discusses the association of drug response with mutational status, indicating that specific mutations, including those in splicing components like serine/arginine rich 2 (ZRSR2), correlate with sensitivity to several drugs. This suggests that the presence of these mutations can predict the effectiveness of certain therapies in acute myeloid leukemia (AML) patients.

Diagnostic, Prognostic evidence:

Diagnostic: The abstract discusses how acute myeloid leukemia (AML) with t(8;21) or inv(16) are recognized as unique entities within AML, indicating that these variants are used to classify and define specific subtypes of the disease.

Prognostic: The abstract mentions that high KIT mutant allele ratios define a group of t(8;21) AML patients with poor prognosis, and that mutations in epigenetic modifying or cohesin genes were associated with a poor prognosis, indicating a correlation with disease outcome independent of therapy.

Diagnostic, Prognostic evidence:

Diagnostic: The abstract states that "only MDS with SF3B1 K700E mutations have a favorable prognosis," indicating that this specific variant is used to classify and define a subtype of myelodysplastic syndromes (MDS).

Prognostic: The results section mentions that "Only SF3B1 Mutation involving K700E Independently Predicts Overall Survival in Myelodysplastic Syndromes," which correlates the K700E variant with disease outcome, specifically overall survival, independent of therapy.

Predictive, Diagnostic evidence:

Predictive: The study reports that the HER2 A775dupYVMA mutation was present in a significant portion of patients and correlates with an objective response rate (ORR) of 20.0%, indicating its association with treatment response to poziotinib in NSCLC.

Diagnostic: The HER2 A775dupYVMA mutation is described as the most frequent mutation in the cohort, suggesting its role in defining or classifying the disease subtype of HER2 exon 20 insertion NSCLC.

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Diagnostic, Functional evidence:

Diagnostic: The study classifies six new BRCA2 variants as pathogenic or nonpathogenic based on genetic information from families, indicating that these variants are used to define or classify the disease relevance of BRCA2 mutations.

Functional: The study evaluates a homology-directed DNA break repair (HDR) functional assay to infer the clinical relevance of BRCA2 variants, demonstrating that the assay alters the understanding of the variants' pathogenicity based on their molecular function.

Oncogenic evidence:

Oncogenic: The abstract states that EZH2 has oncogenic activity and that its mutations result in premature chain termination or abrogation of histone methyltransferase activity, suggesting a role in tumor development for myeloid malignancies. This indicates that the EZH2 mutations contribute to tumor progression in this context.

Oncogenic evidence:

Oncogenic: The study discusses how oncogenic RAS mutations, specifically HrasG12V, are involved in thyroid tumor development, indicating that these somatic variants contribute to tumor progression. The evidence is supported by the use of transposon mutagenesis to identify additional genetic alterations that cooperate with RAS mutations in thyroid carcinogenesis.

Predictive, Oncogenic evidence:

Predictive: The study discusses how exportin-1 inhibition enhances chemosensitivity and demonstrates synergy with chemotherapy agents, indicating that the variant correlates with response to specific therapies in small cell lung cancer (SCLC). This suggests a potential predictive role for the variant in treatment outcomes.

Oncogenic: The research highlights that exportin-1 (XPO1) is highly expressed in SCLC and that its knockout enhances chemosensitivity, implying that the variant contributes to tumor development or progression in this aggressive malignancy.

Predictive, Oncogenic evidence:

Predictive: The study discusses the efficacy of MET-targeted therapies in MET-amplified and MET exon 14 deletion mutant non-small cell lung cancers, indicating that the presence of these variants correlates with response to specific therapies, particularly MET tyrosine kinase inhibitors. The mention of drug resistance mechanisms further emphasizes the predictive nature of the variant's role in treatment outcomes.

Oncogenic: The study assesses secondary MET mutations that likely emerge in response to treatment, suggesting that these somatic variants contribute to tumor development or progression, particularly in the context of resistance to MET-targeted therapies. The use of mutagenesis assays to evaluate these mutations supports their role in oncogenesis.

Predictive, Prognostic evidence:

Predictive: The study indicates that STK11 and KEAP1 mutations are associated with significantly worse progression-free and overall survival to immunotherapy specifically among KRASMUT lung adenocarcinoma patients, suggesting a correlation with treatment response.

Prognostic: The presence of STK11 and KEAP1 mutations correlates with worse overall survival outcomes, as indicated by the hazard ratios provided for both mutations in the context of immunotherapy, independent of any specific treatment.

Predictive evidence:

Predictive: The abstract states that "Abivertinib of 300 mg twice a day demonstrated favorable clinical efficacy" specifically in patients with "EGFR T790M+ NSCLC," indicating that the T790M variant correlates with a positive response to this therapy.

Oncogenic, Functional evidence:

Oncogenic: The study reports that the p.M90I mutation in the RIT1 gene induces cellular transformation in vitro and in vivo, indicating that it contributes to tumor development in lung adenocarcinoma. This aligns with the definition of an oncogenic variant, as it demonstrates the mutation's role in promoting cancer progression.

Functional: The abstract mentions that the mutations in the RIT1 gene, including p.M90I, cluster in a hotspot near the switch II domain, which is involved in GTP hydrolysis. This suggests that the mutation alters the molecular function of the protein, supporting its classification as functional evidence.

Functional evidence:

Functional: The study characterizes the BCL-xL-p53 complex and modulates it through mutagenesis to determine the contributions of BCL-xL's interactions with p53, indicating that the variant alters molecular interactions and functions related to apoptosis.

Functional evidence:

Functional: The study investigates how known tumor-derived missense mutations in the TP53 gene affect the stability and oligomeric structure of the p53 protein, indicating that these mutations alter the molecular function of p53, particularly its ability to form a tetrameric structure essential for its tumor suppressor activity. The analysis of the stability of mutant peptides and their impact on protein interactions and DNA binding further supports this classification.

Diagnostic, Prognostic evidence:

Diagnostic: The K27M mutation is used to define two subgroups of diffuse intrinsic pontine gliomas, indicating its role in classifying the disease and its subtypes.

Prognostic: The mention of different prognosis associated with the K27M mutations suggests that this variant correlates with disease outcome, independent of therapy.

Diagnostic, Prognostic evidence:

Diagnostic: The K27M mutation is used to define two subgroups of diffuse intrinsic pontine gliomas, indicating its role in classifying the disease and its subtypes.

Prognostic: The mention of different prognosis associated with the K27M mutations suggests that this variant correlates with disease outcome, independent of therapy.

Diagnostic, Prognostic, Oncogenic evidence:

Diagnostic: The abstract states that diffuse midline glioma with an H3 K27M mutation was added to the WHO classification as a new grade IV entity, indicating that the presence of the H3 K27M mutation is used to classify and define a specific disease subtype.

Prognostic: The study discusses the outcomes of patients with double mutations, noting that despite the presence of H3 K27M mutations, these cases have a better spontaneous outcome than classic diffuse midline H3 K27M-mutant glioma, suggesting a correlation with disease outcome.

Oncogenic: The abstract mentions that the H3 K27M mutation can occur in association with the BRAF V600E mutation in grade I glioneuronal tumors, indicating that this somatic variant contributes to tumor development or progression.

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Diagnostic, Oncogenic evidence:

Diagnostic: The abstract states that nearly 80% of DIPGs harbor a K27M mutation, indicating its association with this specific disease, which supports its use as a biomarker for diagnosis and classification of DIPG.

Oncogenic: The mention of frequent histone 3 mutations (K27M-H3) in DIPG suggests that this somatic variant contributes to tumor development, as it is implicated in the unique genetic landscape of this aggressive brain cancer.

Diagnostic, Oncogenic evidence:

Diagnostic: The abstract states that nearly 80% of DIPGs harbor a K27M mutation, indicating its association with the disease and suggesting its use as a biomarker for classification.

Oncogenic: The mention of frequent histone 3 mutations (K27M-H3) in DIPG suggests that this somatic variant contributes to tumor development, as it is implicated in the unique genetic landscape of this aggressive brain cancer.

Diagnostic, Oncogenic evidence:

Diagnostic: The abstract states that nearly 80% of DIPGs harbor a K27M mutation, indicating its association with the disease and suggesting its use as a biomarker for classification.

Oncogenic: The mention of frequent histone 3 mutations (K27M-H3) in DIPG suggests that this somatic variant contributes to tumor development, as it is implicated in the unique genetic makeup of this aggressive brain cancer.

Prognostic, Oncogenic evidence:

Oncogenic: The K27M mutation in histone H3.3 is described as being present in approximately 70% of DIPGs and is likely relevant for tumorigenesis, indicating its role in cancer development. The mention of its high frequency and association with specific genetic alterations further supports its oncogenic potential.

Prognostic: The study reports that the K27M mutation confers a worse overall survival compared to H3.3 wild-type patients, indicating that this variant is associated with disease outcome independent of therapy. This correlation with survival outcomes classifies it as prognostic evidence.

Prognostic, Oncogenic evidence:

Oncogenic: The K27M mutation in histone H3.3 is described as being present in approximately 70% of DIPGs, indicating its significant role in tumor development. The mention of its association with dysregulation of the PRC2 complex and its high frequency in tumors supports its contribution to tumorigenesis.

Prognostic: The study reports that the K27M mutation confers a worse overall survival compared to H3.3 wild-type patients, indicating that this variant is associated with disease outcome independent of therapy. This correlation with survival outcomes classifies it as prognostic evidence.

Prognostic, Oncogenic evidence:

Oncogenic: The K27M mutation in histone H3.3 is described as being present in approximately 70% of DIPGs and is likely relevant for tumorigenesis, indicating its role in cancer development. The mention of its high frequency and association with specific genetic alterations further supports its oncogenic potential.

Prognostic: The study reports that the K27M mutation confers a worse overall survival compared to H3.3 wild-type patients, indicating that this variant is associated with disease outcome independent of therapy. This correlation with survival outcomes classifies it as prognostic evidence.

Diagnostic, Oncogenic evidence:

Diagnostic: The K27M mutation in histone H3.3 is used to define clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas, indicating its role in classifying the disease.

Oncogenic: The mention of the K27M mutation in histone H3.3 suggests that it contributes to tumor development or progression, particularly in the context of pediatric diffuse intrinsic pontine gliomas.

Diagnostic, Oncogenic evidence:

Diagnostic: The K27M mutation in histone H3.3 is used to define clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas, indicating its role in classifying the disease.

Oncogenic: The mention of the K27M mutation in histone H3.3 suggests that it contributes to tumor development or progression, particularly in the context of pediatric diffuse intrinsic pontine gliomas.

Oncogenic, Functional evidence:

Oncogenic: The abstract indicates that the p.Lys27Met substitution in histone H3 variants is associated with pediatric midline high-grade astrocytomas (mHGAs), suggesting that this somatic variant contributes to tumor development or progression. The mention of specific mutations and their association with tumor location further supports the oncogenic role of this variant in the context of these tumors.

Functional: The study discusses how the p.Lys27Met alteration is linked to hyperactivation of the BMP-ACVR1 pathway and increased levels of phosphorylated SMAD proteins, indicating that this variant alters molecular or biochemical function within the tumor cells. This suggests a functional impact of the variant on the signaling pathways involved in tumor biology.

Oncogenic, Functional evidence:

Oncogenic: The abstract discusses how the p.Lys27Met substitution in histone H3 variants is associated with pediatric midline high-grade astrocytomas (mHGAs) and highlights its role in driving the epigenetic phenotype of these tumors, indicating that this variant contributes to tumor development or progression.

Functional: The study mentions that the p.Lys27Met alteration is associated with hyperactivation of the BMP-ACVR1 developmental pathway and increased levels of phosphorylated SMAD proteins, suggesting that this variant alters molecular or biochemical function in tumor cells.

Diagnostic, Functional evidence:

Diagnostic: The abstract states that the glycine-to-arginine alteration at codon 34 (G34R) within H3F3A occurs exclusively in pediatric glioblastomas, indicating its use in defining or classifying a specific disease subtype. The mention of the mutation's presence in a certain percentage of glioma cases further supports its role as a diagnostic marker.

Functional: The study investigates alterations in histone methylation in G34R-mutant samples, suggesting that this variant affects molecular functions related to histone modification. This indicates that the G34R mutation alters biochemical processes within the tumor cells.

Diagnostic, Functional evidence:

Diagnostic: The abstract states that the glycine-to-arginine alteration at codon 34 (G34R) within H3F3A occurs exclusively in pediatric glioblastomas, indicating its use in defining or classifying a specific disease subtype. The mention of the mutation's presence in tumor samples from patients further supports its diagnostic relevance.

Functional: The study investigates alterations in histone methylation in G34R-mutant samples, suggesting that this variant affects molecular functions related to histone modification. The analysis of histone methylation patterns indicates that the G34R mutation may alter biochemical functions within the tumor context.

Diagnostic, Prognostic evidence:

Diagnostic: The study suggests that the presence of the H3.3 G34 mutation should be recommended as a routine diagnostic marker for supratentorial CNS tumors across a broad histological spectrum, indicating its role in defining and classifying these tumors.

Prognostic: The survival analysis identified the presence of amplified oncogene(s) and MGMT methylation as independent prognostic markers for poor and favorable outcomes, respectively, indicating that the H3 G34 mutation may correlate with disease outcomes.

Diagnostic, Prognostic evidence:

Diagnostic: The study suggests that the H3.3 G34 mutation should be recommended as a routine diagnostic marker for supratentorial CNS tumors across a broad histological spectrum, indicating its role in defining and classifying these tumors.

Prognostic: The survival analysis identified the presence of amplified oncogene(s) and MGMT methylation as independent prognostic markers for poor and favorable outcomes, respectively, indicating that the H3 G34 mutation may correlate with disease outcomes.

Diagnostic, Oncogenic evidence:

Diagnostic: The abstract states that "each H3F3A mutation defines an epigenetic subgroup of GBM with a distinct global methylation pattern," indicating that these mutations are used to classify and define specific subtypes of glioblastoma.

Oncogenic: The abstract mentions that the H3F3A mutations "give rise to GBMs in separate anatomic compartments," suggesting that these somatic mutations contribute to tumor development and progression in glioblastoma.

Diagnostic, Oncogenic evidence:

Diagnostic: The study identifies recurrent H3F3A mutations that define distinct epigenetic subgroups of glioblastoma (GBM), indicating that these mutations are used to classify the disease into specific subtypes based on their unique methylation patterns.

Oncogenic: The H3F3A mutations are implicated in the development of GBMs, as the study demonstrates that these mutations contribute to tumor formation in separate anatomic compartments, suggesting their role in tumor progression.

Diagnostic, Oncogenic evidence:

Diagnostic: The study identifies recurrent H3F3A mutations that define distinct epigenetic subgroups of glioblastoma (GBM), indicating that these mutations are used to classify the disease into specific subtypes based on their unique methylation patterns.

Oncogenic: The H3F3A mutations are implicated in the development of GBMs, as the study demonstrates that these mutations contribute to tumor formation in separate anatomic compartments, suggesting a role in tumor progression.

Diagnostic, Prognostic evidence:

Diagnostic: The abstract 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. This suggests that the variant is used to confirm or classify a disease subtype.

Prognostic: The results indicate that patients with H3 K27M-mutant tumors have a poor prognosis, with mean survival times reported for both adults and children. This correlation with adverse outcomes, independent of therapy, supports the classification as prognostic evidence.

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Diagnostic, Oncogenic evidence:

Oncogenic: The BRAF:p.V600E mutation is mentioned as being present in a proportion of low-grade glioneuronal tumors (LGGNTs), indicating its role in tumor development or progression, which aligns with the definition of an oncogenic variant.

Diagnostic: The abstract discusses the presence of the BRAF:p.V600E mutation in sporadic cerebellar pilocytic astrocytomas and its association with the activation of the MAPK/ERK pathway, suggesting its use as a biomarker for classifying these tumors.

Diagnostic, Prognostic evidence:

Diagnostic: The study discusses how pediatric low-grade gliomas (pLGG) can be classified based on their alteration type, indicating that these genetic alterations are used to define and categorize the disease, which aligns with the definition of diagnostic evidence.

Prognostic: The abstract mentions that rearrangement-driven tumors infrequently progressed and rarely resulted in death compared to SNV-driven tumors, suggesting that the type of genetic alteration correlates with disease outcomes, which is indicative of prognostic evidence.

Diagnostic, Prognostic evidence:

Diagnostic: The study discusses how pediatric low-grade gliomas (pLGG) can be classified based on their alteration type, indicating that these genetic alterations are used to define and categorize the disease. The mention of different clinical-molecular correlates further supports the use of these variants in diagnosing and stratifying pLGG subtypes.

Prognostic: The abstract notes that rearrangement-driven tumors are diagnosed at a younger age, infrequently progress, and rarely result in death compared to SNV-driven tumors, suggesting that these variants correlate with disease outcomes independent of therapy. This classification into risk categories indicates a prognostic value associated with the different alteration types in pLGG.

Diagnostic, Prognostic evidence:

Diagnostic: The study discusses how pediatric low-grade gliomas (pLGG) can be classified based on their alteration type, indicating that these genetic alterations are used to define and classify the disease and its subtypes. The mention of clinical-molecular correlates further supports the use of these variants in diagnosing and stratifying pLGG into risk categories.

Prognostic: The abstract notes that rearrangement-driven tumors infrequently progressed and rarely resulted in death compared to SNV-driven tumors, suggesting that the type of genetic alteration correlates with disease outcomes independent of therapy. This indicates a prognostic relationship between the variant types and clinical outcomes in pLGG.

Diagnostic, Prognostic evidence:

Diagnostic: The study discusses how pediatric low-grade gliomas (pLGG) can be classified based on their alteration type, indicating that these genetic alterations are used to define and classify the disease and its subtypes. The mention of "broadly classified based on their alteration type" supports the use of these variants in diagnosing and categorizing the tumors.

Prognostic: The abstract notes that rearrangement-driven tumors "infrequently progressed, and rarely resulted in death" compared to SNV-driven tumors, suggesting that the presence of specific variants correlates with disease outcomes independent of therapy. This indicates a prognostic value of the variants in predicting clinical outcomes for patients with pLGG.

Diagnostic, Oncogenic evidence:

Diagnostic: The study discusses the frequency of the BRAF p.V600E variant in various types of glial tumors, indicating its association with specific tumor subtypes, which supports its use as a biomarker for diagnosis and classification of these tumors.

Oncogenic: The presence of the BRAF p.V600E variant is noted in multiple tumor types, suggesting its role in tumor development and progression, which aligns with the definition of an oncogenic variant.

Predictive, Oncogenic evidence:

Predictive: The abstract discusses the patient's response to combination targeted therapy with a selective BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib), indicating that the presence of the BRAF p.T599dup mutation is associated with a positive clinical response to this treatment regimen.

Oncogenic: The mention of the BRAF p.T599dup mutation in the context of a ganglioglioma suggests that this somatic variant contributes to tumor development or progression, as it is associated with a specific tumor type and treatment response.

Predictive, Oncogenic evidence:

Predictive: The abstract mentions that midostaurin has been approved for KIT D816V-positive systemic mastocytosis, indicating that this variant correlates with a specific therapy, demonstrating its predictive value in treatment response.

Oncogenic: The abstract discusses the presence of the KIT D816V mutation in the context of oncogenic receptor tyrosine kinases, suggesting that this somatic variant contributes to tumor development or progression, which aligns with the definition of oncogenic evidence.

Predictive, Oncogenic evidence:

Oncogenic: The BRAFG469V mutation was identified as the only known oncogenic mutation in the patient-derived xenograft model, indicating its role in tumor development. Additionally, the study confirmed that small interfering RNA knockdown of BRAF, but not EGFR, resulted in cell death, further supporting BRAFG469V as an oncogenic driver.

Predictive: The study demonstrated that the BRAFG469V mutation is sensitive to multiple EGFR tyrosine kinase inhibitors (TKIs), suggesting that this variant correlates with response to therapy. The findings indicate that clinically approved EGFR TKIs can be repurposed for treating patients with lung cancer harboring the BRAFG469V mutation.

Predictive, Prognostic evidence:

Prognostic: The study mentions that FLT3 mutations, including point mutations within the tyrosine kinase domain, are associated with short relapse-free and overall survival, indicating a correlation between these mutations and disease outcomes.

Predictive: The abstract discusses the transient clinical responses to FLT3 kinase inhibitors and the high rates of relapse and drug resistance, suggesting that the presence of specific mutations, such as those in the tyrosine kinase domain, can influence treatment response and resistance to therapy.

Diagnostic, Oncogenic, Functional evidence:

Functional: The study reports that the C124S variant is "both protein- and lipid-phosphatase catalytically inactive," indicating that it alters the molecular function of the PTEN protein. This suggests a direct impact on the biochemical activity of the protein, which is a key aspect of functional evidence.

Diagnostic: The abstract mentions that mutations in PTEN, including C124S, have been associated with various human diseases, including autism spectrum disorder and cancer. This association implies that the variant can be used to classify or define these diseases, supporting its classification as diagnostic.

Oncogenic: The results indicate that C124S has been found in somatic cancer, suggesting that this variant contributes to tumor development or progression. This aligns with the oncogenic evidence type, as it demonstrates a direct link between the variant and cancer.

Predictive, Diagnostic evidence:

Predictive: The study discusses FGFR1 amplification (FGFR1amp) as being associated with resistance to endocrine therapy and CDK4/6 inhibitors, indicating that the variant correlates with treatment response. Additionally, it mentions that high FGFR1-4 mRNA levels are associated with FGFRi response, further supporting its predictive nature regarding therapy outcomes.

Diagnostic: FGFR1 amplification is described as recurrent in metastatic breast cancer (MBC) and is used to identify responders to FGFR inhibitors and multi-tyrosine kinase inhibitors, indicating its role in classifying and defining a specific subtype of breast cancer. This association with a specific disease context supports its classification as a diagnostic evidence type.

Oncogenic, Functional evidence:

Functional: The study provides evidence that the BRCA1 missense variant p.L1363P disrupts the interaction with PALB2, leading to defects in homologous recombination repair (HRR) and increased sensitivity to DNA-damaging agents, indicating an alteration in molecular function.

Oncogenic: The results demonstrate that the Brca1 p.L1363P variant accelerates the development of mammary tumors in a mouse model, suggesting that this somatic variant contributes to tumor development and progression.

Predictive, Diagnostic, Prognostic evidence:

Predictive: The study discusses how the presence of the EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor progression-free survival (PFS), indicating that these variants may correlate with treatment response to brigatinib versus crizotinib.

Prognostic: The results mention that the median overall survival was not reached in either treatment group, but there was a suggested survival benefit for brigatinib in patients with baseline brain metastases, indicating a correlation with disease outcome independent of therapy.

Diagnostic: The presence of the EML4-ALK fusion variant 3 is used to assess clinical efficacy and is associated with poor PFS, suggesting its role in defining or classifying the disease in the context of treatment response.

Predictive evidence:

Predictive: The abstract indicates that adavosertib improved progression-free survival (PFS) in patients with RAS/TP53-mutant metastatic colorectal cancer (mCRC), suggesting a correlation between the RAS/TP53 mutations and response to this specific therapy. This aligns with the definition of predictive evidence, as it discusses treatment response in relation to the variant.

Oncogenic, Functional evidence:

Functional: The study discusses how mutations in the N-terminal region of PTEN, including Lys13, affect its PIP3 phosphatase activity and nuclear localization, indicating that these variants alter the molecular function of PTEN. The mention of monoubiquitylation of Lys13 being required for PTEN nuclear entry further supports this classification.

Oncogenic: The abstract and results highlight the role of PTEN as a tumor suppressor and its involvement in tumor progression when its nuclear localization is lost, suggesting that mutations in this region, including those at position 13, contribute to tumor development or progression. The association of PTEN's functions with cancer outcomes reinforces its oncogenic relevance.

Functional evidence:

Functional: The study discusses the D92N mutation and its partial activity, indicating that this variant alters the biochemical function of the PTEN protein, specifically its phosphatase activity. The mention of the mutation's impact on PTEN function supports its classification as a functional variant.

Prognostic evidence:

Prognostic: The study reports that high-grade mucinous adenocarcinoma (high-MC) is significantly associated with shorter disease-free survival (DFS) and overall survival (OS) periods compared to low-grade mucinous adenocarcinoma (low-MC) and nonmucinous carcinoma, indicating that high-MC serves as an independent prognostic factor in colorectal cancer (CRC).

Predictive, Oncogenic evidence:

Predictive: The study discusses the efficacy of onvansertib, a PLK1 inhibitor, in inhibiting tumor growth in Group 3 medulloblastoma, indicating its potential as a therapeutic strategy. The mention of "tumor growth inhibition" and "IC50 concentrations" suggests a correlation with treatment response, which aligns with predictive evidence.

Oncogenic: The abstract states that PLK1 is an "oncogenic kinase" and is overexpressed in Group 3 medulloblastoma, indicating its role in tumor development and progression. This supports the classification of the variant as oncogenic due to its contribution to cancer biology.

Predictive evidence:

Predictive: The study demonstrates a correlation between SNAI2 expression levels and radiosensitivity, indicating that SNAI2 could potentially predict clinical responses to ionizing radiation treatment in rhabdomyosarcoma. This suggests that modulation of SNAI2 levels may influence treatment outcomes, aligning with the predictive evidence type.

Predictive, Functional evidence:

Predictive: The study identifies somatic missense mutations in the ERCC2 gene as being associated with improved response to cisplatin-based chemotherapy in muscle-invasive bladder cancer (MIBC), indicating that these mutations can serve as predictive biomarkers for treatment response.

Functional: The research demonstrates that introducing an ERCC2 mutation into a bladder cancer cell line abrogates nucleotide excision repair (NER) activity, highlighting the functional impact of these mutations on molecular processes related to cisplatin sensitivity.

Predictive, Oncogenic evidence:

Predictive: The study discusses how treatment with KRAS G12C inhibitors, such as sotorasib, can lead to substantial tumor regression in patients with non-small cell lung cancer (NSCLC), indicating a correlation between the G12C variant and response to therapy. Additionally, the exploration of dual blockade of MET and KRAS G12C as a treatment option suggests that the variant's presence influences treatment strategies.

Oncogenic: The presence of the KRAS G12C variant is implicated in the development of resistance mechanisms in NSCLC, as the study identifies subclonal evolution and MET amplification in KRAS G12C NSCLC cells that have developed resistance, indicating that this variant contributes to tumor progression. The mention of tumor shrinkage in xenograft models further supports the oncogenic role of the G12C variant.

Predictive evidence:

Predictive: The study discusses the efficacy of the erlotinib plus bevacizumab regimen in patients with advanced non-small cell lung cancer (NSCLC), specifically noting that progression-free survival (PFS) was significantly improved in patients with untreated metastatic EGFR-mutated NSCLC. This indicates a correlation between the EGFR mutation and response to the combined therapy, classifying it as predictive evidence.

Predictive, Oncogenic evidence:

Oncogenic: The abstract states that the G63R mutation, along with other EGFR mutants, is oncogenic and able to transform cells in a ligand-independent manner, indicating its role in tumor development.

Predictive: The abstract mentions that a subset of EGFR mutations, including G63R, can serve as genomic predictors for response to anti-EGFR antibodies, suggesting that this variant correlates with treatment response.

Predictive, Oncogenic evidence:

Predictive: The study discusses the anticancer activity of sotorasib in patients with KRAS p.G12C-mutated advanced solid tumors, indicating a correlation between the presence of this variant and the response to therapy. The mention of "objective response" and "response to sotorasib therapy" supports this classification.

Oncogenic: The variant p.G12C is implicated in the context of advanced non-small-cell lung cancer (NSCLC), suggesting that it contributes to tumor development or progression. The study focuses on patients with this specific mutation, which is known to drive oncogenic processes in cancer.

Predictive, Oncogenic evidence:

Predictive: The study discusses the anticancer activity of sotorasib in patients with KRAS p.G12C-mutated advanced solid tumors, indicating a correlation between the presence of this variant and the response to therapy. The mention of "objective response" and "response to sotorasib therapy" supports this classification.

Oncogenic: The variant p.G12C is implicated in the context of advanced non-small-cell lung cancer (NSCLC), suggesting that it contributes to tumor development or progression, which aligns with the definition of an oncogenic variant. The study focuses on the specific mutation in relation to cancer treatment, reinforcing its role in oncogenesis.

Oncogenic evidence:

Oncogenic: The study demonstrates that the NFASC-NTRK1 fusion gene contributes to tumor formation in glioblastoma multiforme, as evidenced by increased proliferation, colony formation, and tumor formation in vivo, indicating its role in tumor development or progression.

Diagnostic, Oncogenic evidence:

Diagnostic: The abstract mentions that mutations in JAK2V617F co-occur with other oncogenic mutations in hematological malignancies, indicating its role in defining or classifying a disease subtype. This suggests that the presence of JAK2V617F is associated with specific malignancies, supporting its use as a diagnostic marker.

Oncogenic: The variant JAK2V617F is described in the context of co-occurring with other oncogenic mutations, implying its contribution to tumor development or progression in hematological malignancies. This association with oncogenic tyrosine kinases indicates that JAK2V617F plays a role in the pathogenesis of these cancers.

Predictive evidence:

Predictive: The study found that mutations in the TP53 gene, particularly those affecting loop domains L2 or L3 of the p53 protein, were associated with a lack of response to chemotherapy, indicating that these mutations may predict resistance to specific treatment regimens in breast cancer.

Predictive, Prognostic evidence:

Predictive: The study indicates that TP53 mutations, particularly those affecting the L2 or L3 domains, are associated with a lack of response to doxorubicin chemotherapy, suggesting that these mutations can predict resistance to this specific treatment. The statistical significance of the association (P = 0.008 for mutations affecting L2/L3) further supports this predictive evidence.

Prognostic: The findings also show that TP53 mutations, along with histological grade and bcl-2 expression, predict relapse-free and breast cancer-specific survival, indicating that these mutations correlate with disease outcomes independent of therapy. The statistical significance of the associations (Ps between <0.0001 and 0.0155) reinforces the prognostic value of TP53 mutations in this context.

Diagnostic, Predisposing evidence:

Predisposing: The study discusses germline mutations in the PTEN gene associated with PTEN hamartoma tumour syndrome (PHTS), which confers an inherited risk for developing various cancers, including breast and thyroid cancers. The mention of "germline mutations" indicates that the variant is inherited, thus fitting the predisposing category.

Diagnostic: The abstract states that PTEN mutations are used to define and classify PHTS, which encompasses several clinical syndromes. This indicates that the variant is associated with a specific disease, fulfilling the criteria for diagnostic evidence.

Diagnostic evidence:

Diagnostic: The variant p.Cys211X is mentioned in the context of tumor samples and is associated with specific histologic types and grades, indicating its role in defining or classifying a disease subtype. This aligns with the use of variants as biomarkers for diagnosis.

Diagnostic, Predisposing evidence:

Diagnostic: The study discusses PTEN germline mutations in the context of PTEN hamartoma tumor syndromes (PHTS), indicating that these mutations are used to classify and confirm the diagnosis of conditions like Bannayan-Riley-Ruvalcaba syndrome and other related syndromes. The mention of PTEN testing in children with specific phenotypic features further supports its role as a diagnostic marker.

Predisposing: The abstract specifies that the PTEN mutation is a germline mutation, which confers inherited risk for developing PHTS, including Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. This aligns with the definition of predisposing evidence, as it highlights the inherited nature of the mutation and its association with disease risk.