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.

Prognostic, Functional evidence:

Prognostic: The study reports that atypical RAS mutations, including KRAS L19F, are associated with worse overall survival in metastatic colorectal cancer (mCRC) compared to RAS/BRAF wild-type, indicating a correlation with disease outcome independent of therapy.

Functional: The study functionally characterized the KRAS L19F variant using in vitro assays, demonstrating that it has varying signaling activity compared to wild-type, which indicates that it alters molecular function.

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.

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 the variants of PIK3CA lead to selective initiation of brain hyperexcitability and remodelling of the synaptic constituency, indicating that these variants alter molecular or biochemical functions within the tumor microenvironment.

Predictive, Oncogenic evidence:

Predictive: The abstract states that "PIK3CA mutation confers resistance to chemotherapy in TNBC," indicating that the E545K variant is associated with treatment resistance, which aligns with the predictive evidence type.

Oncogenic: The results mention that "mutations in PIK3CA induce sustained activation of AKT through the PI3K/AKT/mTOR pathway," suggesting that the E545K variant contributes to tumor development and progression, which is characteristic of oncogenic evidence.

Predictive, Oncogenic evidence:

Predictive: The abstract states that "PIK3CA mutation confers resistance to chemotherapy in TNBC," indicating that the E545K variant is associated with treatment resistance, which aligns with the predictive evidence type.

Oncogenic: The results mention that "mutations in PIK3CA induce sustained activation of AKT through the PI3K/AKT/mTOR pathway," suggesting that the E545K variant contributes to tumor development and progression, which is characteristic of oncogenic evidence.

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.

nan evidence:

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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.