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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 evidence:

Missing abstract

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.

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 evidence:

Missing abstract

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 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.

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.

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 evidence:

Missing abstract

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

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.

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.

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.

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 evidence:

Missing abstract

nan evidence:

Missing abstract

nan evidence:

Missing abstract

Predictive, Diagnostic, Oncogenic evidence:

Diagnostic: The mention of "MET exon 14 skipping defined a new molecular subset of NSCLC" indicates that this variant is used to classify a specific subtype of the disease, which aligns with the diagnostic evidence type.

Predictive: The statement "The therapeutic EGFR inhibitors might be an alternative treatment for patients with MET mutant NSCLC" suggests a correlation between the presence of the MET mutation and the response to therapy, indicating predictive evidence.

Oncogenic: The phrase "T790M mutations in EGFR mutant lung tumors with acquired resistance" implies that the T790M variant contributes to tumor progression and resistance mechanisms, supporting its classification as oncogenic.

Predictive, Oncogenic evidence:

Predictive: The study evaluates the response to MET inhibitor therapy with crizotinib in a patient with advanced pulmonary sarcomatoid carcinoma (PSC) carrying a MET exon 14 skipping mutation, indicating that this variant correlates with sensitivity to a specific therapy. The dramatic response observed in the patient further supports the predictive nature of the MET exon 14 skipping mutation in relation to treatment outcomes.

Oncogenic: The functional studies conducted in lung adenosquamous and gastric adenocarcinoma cell lines demonstrate that MET exon 14 skipping has oncogenic roles, contributing to tumor development and progression. This is evidenced by the marked effects on cell viability and downstream signaling pathways when MET is silenced or inhibited.

Diagnostic, Prognostic, Oncogenic evidence:

Diagnostic: The METDelta14 mutation was detected in specific subtypes of non-small cell lung carcinoma (NSCLC), indicating its association with certain cancer types, particularly sarcomatoid carcinoma, which suggests its role in classifying and defining disease subtypes.

Oncogenic: The METDelta14 mutation is described as an oncogenic alteration that contributes to tumor development, as evidenced by its detection in a significant percentage of NSCLC cases and its association with higher MET protein expression.

Prognostic: The study identifies METDelta14 and high-level amplification as independent prognostic factors that predict poorer survival outcomes, indicating their relevance in assessing disease prognosis.

Predictive, Diagnostic evidence:

Diagnostic: The study identifies the presence of the METex14del variant in various cancer types, indicating its association with specific malignancies such as gastric cancer, colon cancer, and non-small cell lung cancer. This suggests that the variant can be used to classify or confirm the presence of these diseases.

Predictive: The results demonstrate that tumor-derived cell lines from METex14del+ patients showed substantial growth inhibition when treated with MET tyrosine kinase inhibitors and a monoclonal antibody targeting MET. This indicates that the variant may correlate with sensitivity to specific therapies, suggesting its potential as a predictive biomarker for treatment response.

Functional evidence:

Functional: The study discusses the correlation between cytosine to thymine (C >T) transition frequency and other mutation types, indicating that the variant may influence molecular mechanisms related to mutation patterns. This suggests that the C >T variant could alter biochemical functions, as it is involved in the broader context of mutation frequency and its relationship with other genomic changes.

Oncogenic evidence:

Oncogenic: The variant M1124D of MET is mentioned as a known activating mutation that is confirmed to induce lung adenocarcinoma, indicating its role in tumor development or progression. This classification is supported by the context in which the mutation is discussed, highlighting its contribution to cancer.

Predictive, Oncogenic evidence:

Oncogenic: The study discusses MET activation through gene amplification and splice mutations in lung adenocarcinomas, indicating that these somatic variants contribute to tumor development in this cancer type. The mention of "activated MET" driving approximately 5% of pulmonary adenocarcinomas supports the classification as oncogenic.

Predictive: The conclusion states that patients with activated MET would be candidates for targeted therapy against MET, suggesting a correlation between the variant and response to a specific therapy. This aligns with the predictive evidence type as it indicates potential treatment implications based on the presence of the variant.

Predictive, Oncogenic evidence:

Oncogenic: The abstract discusses c-Met alterations, including the E168D variant, in the context of non-small cell lung cancer (NSCLC) and indicates that these mutations contribute to tumor development and progression, particularly through the activation of downstream signaling pathways. This suggests that E168D plays a role in the oncogenic behavior of NSCLC.

Predictive: The study highlights the potential of c-Met as a therapeutic target, with evidence that inhibition of c-Met leads to significant reductions in cell viability in NSCLC cells. This indicates that the E168D variant may correlate with response to c-Met-targeted therapies, supporting its predictive value in treatment outcomes.

Oncogenic, Functional evidence:

Oncogenic: The study demonstrates that the R988C mutation in the c-MET gene contributes to tumor development and progression, as it regulates cell proliferation, enhances tumorigenicity, and increases cell motility and migration in SCLC cell lines. This indicates that the mutation has a role in driving cancer behavior, which is characteristic of oncogenic variants.

Functional: The introduction of the R988C mutation into cell lines resulted in altered c-MET RTK signaling, including increased constitutive tyrosine phosphorylation of proteins, which suggests that this variant affects molecular function and signaling pathways. This alteration in biochemical activity is indicative of a functional impact of the mutation.

Functional evidence:

Functional: The study discusses how the c-metsm variant transcript leads to an in-frame deletion of 47 amino acids in the juxtamembrane region of the cytoplasmic domain, which alters the molecular function of the c-Met protein. The presence of a sequence motif for protein kinase C phosphorylation in the deleted region suggests that this variant may impact the kinase activity of the receptor, indicating a functional alteration.

Predictive, Oncogenic evidence:

Oncogenic: The study discusses somatic intronic mutations of the Met kinase that contribute to tumor growth in lung cancer, indicating that these mutations play a critical role in oncogenesis by altering receptor down-regulation and enhancing ligand-mediated proliferation.

Predictive: The findings suggest that the presence of the Met deletion leads to sustained activation of the receptor and downstream signaling, which correlates with enhanced tumor growth and indicates potential sensitivity to a Met antagonist, highlighting the predictive nature of this variant in response to therapy.

Predictive, Oncogenic evidence:

Oncogenic: The abstract discusses MET exon 14 splicing abnormalities as a "new potential oncogenic driver" and mentions that these alterations have been validated across different cancer subtypes, indicating their role in tumor development and progression.

Predictive: The abstract highlights the clinical activity of anti-Met-targeted therapy specifically in patients with MET exon 14 skipping lung cancer, suggesting that this variant correlates with response to targeted therapy.

Predictive, Diagnostic, Prognostic, Oncogenic evidence:

Predictive: The study assesses the safety and efficacy of sotorasib, a KRAS G12C inhibitor, in patients with KRAS p.G12C-mutated pancreatic cancer, indicating a correlation between the variant and response to a specific therapy.

Diagnostic: The KRAS p.G12C mutation is mentioned as occurring in approximately 1 to 2% of pancreatic cancers, suggesting its role in defining or classifying a specific subtype of the disease.

Prognostic: The results report median overall survival and progression-free survival for patients with KRAS p.G12C-mutated pancreatic cancer, indicating that the variant correlates with disease outcomes independent of therapy.

Oncogenic: The presence of the KRAS p.G12C mutation is implied to contribute to tumor development in pancreatic cancer, as the study focuses on patients with this specific mutation and their cancer progression.

Predictive, Functional evidence:

Predictive: The study indicates that high expression levels of CXorf67 in tumor cells correlate with increased sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, suggesting a potential therapeutic response when combined with radiotherapy. This aligns with the definition of predictive evidence as it discusses treatment response related to a specific therapy.

Functional: The abstract describes how CXorf67 alters the molecular function by suppressing homologous recombination-mediated DNA repair and inhibiting the interaction between PALB2 and BRCA2. This demonstrates a clear alteration in biochemical function, which supports the classification as functional evidence.

Predictive, Oncogenic evidence:

Predictive: The study discusses how the L1196Q mutation in ALK is associated with resistance to ALK inhibitors crizotinib and alectinib, indicating that this variant correlates with treatment response and resistance. The patient with this mutation achieved a partial response after switching to ceritinib, further supporting the predictive nature of this variant in therapy outcomes.

Oncogenic: The identification of the L1196Q mutation as a secondary mutation that likely alters the binding of ALK inhibitors suggests that it contributes to tumor progression and resistance mechanisms. This aligns with the definition of an oncogenic variant, as it plays a role in the development of resistance in the context of cancer treatment.

nan evidence:

Based on the provided abstract and results section, there is no specific mention of the variant(s) in either section. Therefore, I cannot classify any evidence type as there are no relevant statements to support any of the CIViC evidence types.

Predictive, Diagnostic evidence:

Predictive: The study discusses the response to therapy with osimertinib in a patient harboring EGFR exon 19 deletions and EGFR-SEPT14 fusions, indicating that these variants correlate with treatment response. The mention of achieving clinical remission and long-term survival with specific therapies highlights the predictive nature of these mutations in the context of treatment outcomes.

Diagnostic: The identification of rare EGFR-SEPT14 fusions in the cerebrospinal fluid of the patient suggests that these variants can be used to classify or define a specific subtype of lung adenocarcinoma associated with leptomeningeal metastasis. This classification is crucial for understanding the disease and tailoring treatment strategies.

Oncogenic evidence:

Oncogenic: The study identifies 120 candidate gene fusions within chromothripsis (CT) regions in glioblastoma (GBM), with 30 of these fusions having potential oncogenic activities, indicating that these somatic variants contribute to tumor development or progression.

Oncogenic evidence:

Oncogenic: The study identifies 120 candidate gene fusions within chromothripsis (CT) regions in glioblastoma (GBM), with 30 of these fusions having potential oncogenic activities, indicating that these somatic variants contribute to tumor development or progression.

Oncogenic evidence:

Oncogenic: The study identifies 120 candidate gene fusions within chromothripsis regions in glioblastoma, with 30 of these fusions having potential oncogenic activities, indicating that these somatic variants contribute to tumor development or progression.

Predictive, Diagnostic evidence:

Predictive: The study discusses the efficacy of ivosidenib in patients with IDH1-mutated acute myeloid leukemia (AML), indicating that the presence of the IDH1 mutation correlates with treatment response, as evidenced by the overall response rate of 41.6% and the rates of complete remission. This suggests that the IDH1 mutation is predictive of sensitivity to the therapy being tested.

Diagnostic: The abstract mentions that mutations in the IDH1 gene occur in 6 to 10% of patients with AML, indicating that the presence of the IDH1 mutation can be used to classify or confirm the diagnosis of AML in these patients. This establishes the IDH1 mutation as a relevant biomarker for the disease.

Oncogenic, Functional evidence:

Oncogenic: The study demonstrates that the IDH1 R132H variant promotes cytokine independence and blocks differentiation in hematopoietic cells, indicating its role in tumor development and progression. This suggests that the variant contributes to the oncogenic process in the context of leukemia.

Functional: The research provides evidence that the IDH1 R132H variant alters the biochemical function of isocitrate dehydrogenase, leading to the overproduction of (R)-2-hydroxyglutarate, which is implicated in the pathogenesis of IDH mutant tumors. This alteration in function is critical for understanding the molecular mechanisms by which this variant influences leukemogenesis.

Predictive, Diagnostic evidence:

Diagnostic: The abstract mentions that the study involves patients with an IDH1 mutation, specifically noting that R132C was the most prevalent IDH1 variant among the patients. This indicates that the variant is used to classify or define a specific disease subtype, which aligns with the diagnostic evidence type.

Predictive: The abstract discusses the use of ivosidenib, a therapy targeting mutant IDH1, in patients with cholangiocarcinoma harboring IDH1 mutations. This suggests a correlation between the presence of the R132C variant and the response to treatment with ivosidenib, fitting the predictive evidence type.

Oncogenic evidence:

Oncogenic: The study discusses the use of a genetically engineered mouse model incorporating the mutant KrasG12D, indicating that this somatic variant contributes to tumor development and progression in pancreatic ductal adenocarcinoma (PDAC). The context of the model and its relevance to therapeutic challenges highlights the oncogenic nature of the variant.

Predictive, Prognostic evidence:

Predictive: The abstract states that KRAS mutations are confirmed as predictive biomarkers of response to epidermal growth factor receptor (EGFR)-targeted therapies, indicating a correlation between these mutations and treatment response.

Prognostic: The abstract mentions that mutations in exon 4 of KRAS predict a more favorable clinical outcome in patients with colorectal cancer, suggesting that these mutations are associated with disease outcome independent of therapy.

Oncogenic, Functional evidence:

Oncogenic: The study discusses the role of mutations in the RAS family, including K117, in contributing to neoplastic transformation and cancer, indicating that these variants are associated with tumor development.

Functional: The abstract mentions that computational scores correlate with changes in enzyme activity due to genomic variants, suggesting that K117N may alter biochemical function, which aligns with the definition of functional evidence.

Prognostic, Functional evidence:

Prognostic: The study reports that atypical RAS mutations, including KRAS L19F, had worse overall survival compared to RAS/BRAF wild-type mCRC, indicating a correlation with disease outcome independent of therapy.

Functional: The study functionally characterized the KRAS L19F variant using various assays, demonstrating that it alters signaling pathways, which is indicative of its molecular function in cancer biology.

Prognostic, Functional evidence:

Prognostic: The study reports that atypical RAS mutations, including KRAS L19F, had worse overall survival compared to RAS/BRAF wild-type mCRC, indicating a correlation with disease outcome independent of therapy.

Functional: The study functionally characterized the KRAS L19F variant using various assays, demonstrating that it alters signaling pathways, which supports its classification as a functionally relevant mutation.

Diagnostic, Oncogenic evidence:

Diagnostic: The study characterizes the presence of specific genetic events, such as the ETV6-NTRK3 fusion and EGFR ITD, in different subtypes of congenital mesoblastic nephroma (CMN), indicating their role in defining and classifying these tumors. The mention of "consistent genetic event" and the utility of immunohistochemistry as surrogate markers further supports the diagnostic nature of these variants in CMN.

Oncogenic: The presence of EGFR ITD and ETV6-NTRK3 fusion in various subtypes of CMN suggests that these somatic variants contribute to tumor development or progression, as they are consistently found in the tumor samples analyzed. The study's focus on these genetic alterations in the context of CMN indicates their potential role in oncogenesis.

Predictive, Diagnostic evidence:

Predictive: The study discusses how the presence of the IDH1 R132H mutation may help predict the response to potential therapies, particularly in the context of DNA damage response (DDR) pathways. This suggests a correlation between the variant and sensitivity to therapeutic interventions, aligning with the predictive evidence type.

Diagnostic: The mention of IDH1 R132H in the context of understanding its role in glioma and its association with DDR pathways indicates that this variant can be used to classify or define a specific disease context. This aligns with the diagnostic evidence type as it relates to the identification of disease mechanisms.

Diagnostic, Oncogenic evidence:

Diagnostic: The abstract mentions that the variant ETV6-RET is associated with salivary gland secretory carcinoma (MASC), indicating its role in defining or classifying this specific disease subtype.

Oncogenic: The presence of the ETV6-RET and EGFR-SEPT14 fusions in the tumor is indicative of their contribution to tumor development, as these fusions are characteristic of the neoplasm discussed in the study.

Diagnostic, Oncogenic evidence:

Diagnostic: The abstract discusses the identification of ETV6-RET and EGFR-SEPT14 fusions in salivary gland secretory carcinoma, indicating that these fusions are characteristic of this specific neoplasm and contribute to its molecular profile. This suggests that the presence of these variants can be used to classify or confirm the diagnosis of this tumor type.

Oncogenic: The mention of ETV6-NTRK3 fusions and other ETV6 fusion partners in the context of salivary gland secretory carcinoma implies that these somatic variants contribute to tumor development or progression. The identification of these fusions as characteristic of the carcinoma supports their role in oncogenesis.

Predictive, Diagnostic evidence:

Predictive: The study discusses the patient's response to treatment with erlotinib, an EGFR tyrosine kinase inhibitor, indicating that the presence of the EGFR-SEPT14 fusion may serve as a therapeutic target and correlates with treatment response. The mention of EGFRvIII's involvement in erlotinib resistance further supports the predictive nature of the variant in relation to therapy outcomes.

Diagnostic: The identification of the EGFR-SEPT14 fusion in the patient's colorectal adenocarcinoma suggests its potential use as a biomarker for classification or targeting in colorectal cancer, indicating its role in defining a specific subtype of the disease.

Predictive, Diagnostic evidence:

Predictive: The abstract discusses the patient's treatment with erlotinib, an EGFR tyrosine kinase inhibitor, and notes that the presence of the EGFR-SEPT14 fusion may serve as a therapeutic target, indicating a correlation with treatment response. Additionally, the mention of EGFRvIII being involved in erlotinib resistance suggests a predictive relationship regarding therapy outcomes.

Diagnostic: The identification of the EGFR-SEPT14 fusion in the patient's colorectal cancer highlights its potential use as a biomarker for classification or targeting in treatment, which aligns with the diagnostic evidence type. The report emphasizes the significance of this fusion in the context of colorectal cancer, suggesting its role in defining a subtype of the disease.

Oncogenic, Functional evidence:

Oncogenic: The study discusses the EGFRvIII variant as a common feature in malignant gliomas, indicating its role in tumor development and progression through mechanisms such as increased proliferative capacity and radioresistance in astrocytes. This suggests that EGFRvIII contributes to the oncogenic processes in gliomas, supporting its classification as an oncogenic variant.

Functional: The variant EGFRvIII is shown to alter molecular function by exhibiting ligand-independent autophosphorylation and activating different downstream signaling pathways (ERK and AKT) in astrocytes and fibroblasts. This alteration in signaling and function highlights the functional impact of the EGFRvIII mutation on cellular behavior.

Predictive, Oncogenic evidence:

Predictive: The study discusses how the EGFR tyrosine kinase inhibitors (TKI) efficiently targeted the DeltaN566/DeltaN599-mutant-mediated signaling and prolonged the survival of mice bearing intracranial xenografts, indicating a correlation between these variants and sensitivity to therapy.

Oncogenic: The presence of the DeltaN566 and DeltaN599 mutations, which are described as products of intrachromosomal rearrangements leading to a constitutively active form of EGFR, suggests that these somatic variants contribute to tumor development and progression in ependymomas.

Predictive evidence:

Predictive: The study provides clinical evidence that combined targeted therapy with gefitinib and cetuximab could result in a significant antitumor response in patients with the EGFR-IGR fusion and EGFR amplification, indicating a correlation between the variant and treatment response.

Predictive evidence:

Predictive: The study discusses how chromatin regulatory genes (CRGs) are associated with anthracycline sensitivity, indicating that these genes can predict the response to anthracycline therapy in breast cancer patients. This suggests a correlation between the expression levels of these CRGs and the effectiveness of the treatment, which aligns with the predictive evidence type.

Predisposing, Functional evidence:

Predisposing: The abstract describes multiple lentigines/LEOPARD syndrome (LS) as an "autosomal dominant disorder" caused by "germ line missense mutations in PTPN11," indicating that these mutations are inherited and confer risk for developing the disease.

Functional: The study discusses how LS mutants are "catalytically defective" and act as "dominant negative mutations," which alters the molecular function of the Shp2 protein, suggesting a direct impact on its biochemical activity.

Predictive, Diagnostic, Prognostic evidence:

Predictive: The study indicates that expression of FMO4 and OSBPL3 was associated with treatment response to bevacizumab plus CCNU chemotherapy, suggesting that these markers may help predict which patients will benefit from this specific therapy.

Prognostic: The results show a significant benefit in progression-free survival and a trend toward improved overall survival for tumors assigned to the IGS-18 or "classical" subtype treated with bevacizumab plus CCNU, indicating that these subtypes may correlate with better disease outcomes independent of therapy.

Diagnostic: The study mentions the identification of molecular glioma subtypes, which are used to classify patients and assess their potential benefit from treatment, thus providing evidence for the diagnostic utility of these subtypes in recurrent glioblastoma.

Predictive, Oncogenic evidence:

Predictive: The study indicates that the T790M variant is associated with resistance to first-generation EGFR tyrosine kinase inhibitors and suggests that osimertinib may be effective for patients harboring this variant, highlighting its role in treatment response.

Oncogenic: The presence of the T790M variant is described as an acquired resistance mechanism, which implies its contribution to tumor progression in the context of EGFR-mutated non-small cell lung cancer (NSCLC).

Oncogenic, Functional evidence:

Functional: The abstract discusses how mutations, including the G->A variant, disrupt the function of LZTR-1, which restrains self-renewal and growth of glioma spheres. This indicates that the variant alters molecular function, specifically in the context of glioblastoma.

Oncogenic: The results section mentions that the G->A variant is part of the somatic mutations observed in glioblastoma, which are associated with tumor development and progression. This supports the classification of the variant as contributing to oncogenic processes in cancer.

Predictive, Oncogenic evidence:

Predictive: The study discusses how NOTCH1 mutations (NOTCH1MUT) correlate with sensitivity to PI3K inhibition, indicating that these mutations can influence the response to therapy. The mention of "inhibition of PI3K can selectively target NOTCH1 mutant HNSCC cells" supports this classification as it directly relates to treatment response.

Oncogenic: The abstract highlights that truncating and missense mutations in NOTCH1 are frequent in head and neck squamous cell carcinoma (HNSCC), suggesting that these somatic mutations contribute to tumor development or progression. The context of these mutations being prevalent in a cancer type supports the classification as oncogenic.

Oncogenic, Functional evidence:

Functional: The variant c.3350+1G>T in the PALB2 gene is described as a splicing mutation that disrupts splicing and leads to the loss of RAD51 and BRCA2 binding domains, indicating that it alters the molecular function of the PALB2 protein.

Oncogenic: The study confirms that the PALB2 variant c.3350+1G>T is somatic in origin, contributing to tumor development or progression in the context of pancreatic ductal adenocarcinoma.

Predictive, Diagnostic, Prognostic evidence:

Predictive: The study discusses therapeutic responses and survival outcomes based on DNA methylation molecular grouping, indicating that certain variants, such as FOXR2 activation and BCOR alteration, correlate with treatment responses and survival rates. This aligns with the predictive evidence type as it relates to how these variants influence response to therapy.

Diagnostic: The abstract mentions the reclassification of CNS-PNETs based on methylation profiling, which suggests that these molecular features are used to define and classify the tumors, indicating a diagnostic role for the variants involved. This supports the classification of the evidence as diagnostic since it relates to the identification and categorization of disease subtypes.

Prognostic: The study reports significant survival differences based on DNA methylation molecular grouping, which correlates with disease outcomes independent of therapy. This indicates that the variants discussed have prognostic implications, as they are associated with overall survival rates in the patient cohort.

Diagnostic, Oncogenic evidence:

Diagnostic: The study discusses high-grade neuroepithelial tumors with BCOR exon 15 internal tandem duplication (HGNET BCOR ex15 ITD) as a distinct tumor entity, indicating that this variant is used to classify and define a specific disease subtype within the central nervous system.

Oncogenic: The presence of the BCOR exon 15 internal tandem duplication is described as a solitary pathogenic alteration in several cases, suggesting that it contributes to tumor development or progression in HGNET BCOR ex15 ITD.

Diagnostic, Oncogenic evidence:

Oncogenic: The abstract states that alterations in the BCOR gene, including internal tandem duplications (ITDs) of exon 15, are described as important oncogenic changes that define several diagnostic entities, indicating that these variants contribute to tumor development in specific cancers.

Diagnostic: The abstract mentions that BCOR ITDs have been recurrently described in specific pediatric cancers, such as clear cell sarcoma of the kidney and primitive myxoid mesenchymal tumor of infancy, suggesting that these variants are used to classify and define these diseases.

Diagnostic, Oncogenic evidence:

Oncogenic: The abstract states that alterations in the BCOR gene, including internal tandem duplications (ITDs) of exon 15, are described as important oncogenic changes that define several diagnostic entities, indicating that these variants contribute to tumor development in specific cancers.

Diagnostic: The abstract mentions that BCOR ITDs have been recurrently described in specific pediatric cancers, such as clear cell sarcoma of the kidney and primitive myxoid mesenchymal tumor of infancy, suggesting that these variants are used to classify and define these diseases.

Oncogenic evidence:

Oncogenic: The study identifies recurrent internal tandem duplications in BCOR, which is implicated in the tumorigenesis of clear cell sarcomas of the kidney, indicating that this somatic variant contributes to tumor development or progression.

Oncogenic evidence:

Oncogenic: The study identifies recurrent internal tandem duplications in BCOR, which is described as a key constituent of a variant polycomb repressive complex, suggesting that these alterations contribute to tumor development in clear cell sarcomas of the kidney.

Oncogenic, Functional evidence:

Oncogenic: The study discusses how the lung-enriched p53 mutants V157 and V157F contribute to a gain of function transcriptome in lung cancer, indicating their role in tumor development or progression. This aligns with the evidence that these somatic variants are involved in altering the tumor's behavior.

Functional: The abstract mentions that cell lines with the mutant p53-V157F exhibit a loss of expression of canonical wild-type p53 target genes and regulate genes not previously linked to p53 function, demonstrating an alteration in molecular function. This suggests that the variant affects biochemical pathways and gene regulation in a significant way.

Oncogenic, Functional evidence:

Oncogenic: The study discusses how the lung-enriched p53 mutants V157 and V157F contribute to a gain of function transcriptome in lung cancer, indicating their role in tumor development or progression. This aligns with the evidence that these somatic variants are involved in altering the tumor's behavior.

Functional: The abstract mentions that cell lines with mutant p53-V157F exhibit a loss of expression of canonical wild-type p53 target genes and regulate genes not previously linked to p53 function, demonstrating that the variant alters molecular or biochemical function. This supports the classification of V157F as having functional implications in the context of lung cancer.

Oncogenic evidence:

Oncogenic: The study discusses how the V157F mutation in the p53 gene contributes to tumor cell proliferation and tumor progression, indicating that this somatic variant plays a role in cancer development. The findings suggest that the expression of GEF-H1, which is activated by mutant p53, is crucial for the growth of cells harboring this mutation, supporting its oncogenic potential.

Predictive, Diagnostic, Prognostic, Oncogenic evidence:

Predictive: The abstract mentions that dabrafenib plus trametinib notably improved long-term survival in BRAF V600E-mutant anaplastic thyroid cancer, indicating a correlation between the variant and response to therapy.

Diagnostic: The result section specifies that the study focuses on patients with BRAF V600E-mutant anaplastic thyroid cancer, which implies that the presence of this variant is used to classify and define the disease subtype.

Prognostic: The abstract states that the treatment improved long-term survival, suggesting that the BRAF V600E mutation correlates with disease outcome independent of therapy.

Oncogenic: The context of the study revolves around BRAF V600E as a mutation in anaplastic thyroid cancer, indicating that this somatic variant contributes to tumor development or progression.

Oncogenic, Functional evidence:

Oncogenic: The study identifies several driver variants of PIK3CA that contribute to the molecular properties of glioblastoma, indicating their role in tumor development and progression. The mention of these variants driving gliomagenesis supports their classification as oncogenic.

Functional: The research demonstrates that tumors driven by these PIK3CA variants exhibit selective initiation of brain hyperexcitability and remodelling of the synaptic constituency, indicating that these variants alter molecular or biochemical functions within the tumor microenvironment.