Diagnostic, Predisposing evidence:

Diagnostic: The study identifies RASA1 mutations as the cause of capillary malformation-arteriovenous malformation (CM-AVM), indicating that these mutations are used to define and confirm the clinical diagnosis of the disorder. The mention of screening RASA1 in patients with specific phenotypes further supports its role as a diagnostic marker for CM-AVM.

Predisposing: The abstract describes CM-AVM as an autosomal-dominant disorder caused by heterozygous RASA1 mutations, which implies that these mutations confer inherited risk for developing the disease. The classification of the disorder as autosomal-dominant suggests a germline origin of the RASA1 mutations involved.

Diagnostic, Oncogenic evidence:

Diagnostic: The study discusses RASA1-related disorders and highlights that variants in the RASA1 gene are associated with hereditary capillary malformations and other vascular malformation syndromes, indicating the use of these variants to classify and confirm the disease.

Oncogenic: The mention of deleterious RASA1 variants contributing to the clinical features of vascular malformation syndromes suggests that these somatic variants may play a role in tumor development or progression, particularly in the context of vascular anomalies.

Diagnostic, Oncogenic evidence:

Diagnostic: The study discusses the association of RASA1 mutations with capillary malformation (CM) and related vascular anomalies, indicating that these mutations can be used to classify and confirm the presence of CM-AVM. The mention of "familial segregation of CM" and the identification of a genetic locus further supports its role in disease classification.

Oncogenic: The abstract describes how heterozygous inactivating RASA1 mutations contribute to the development of atypical capillary malformations and associated vascular anomalies, suggesting a role in tumor development or progression. The involvement of p120-RasGAP in signaling pathways that control cell proliferation and survival indicates its potential oncogenic function.

Diagnostic, Oncogenic, Functional evidence:

Diagnostic: The study presents evidence that a germline mutation involving codon 600 of BRAF is associated with the development of cardio-facio-cutaneous (CFC) syndrome, indicating its role in defining a specific disease phenotype.

Oncogenic: The abstract discusses the somatic mutation p.V600E as frequently found in various tumors, suggesting that mutations at codon 600, including p.V600G, contribute to tumor development or progression, particularly in the context of cancer-associated mutations.

Functional: The in vitro analysis demonstrates that the p.V600G mutation alters the molecular function of BRAF by increasing ERK and ELK phosphorylation compared to wild-type BRAF, indicating a change in biochemical activity.

Predictive, Oncogenic evidence:

Predictive: The abstract mentions that the FLT-3/Q575Delta mutation can be targeted using available FLT-3 tyrosine kinase inhibitors (TKIs), indicating a correlation with treatment response. This suggests that the variant is predictive of sensitivity to specific therapies.

Oncogenic: The abstract describes the FLT-3/Q575Delta mutation as activating and driving downstream signaling comparable to the well-known FLT-3/ITD mutation, which is associated with tumor development in acute myeloid leukemia (AML). This indicates that the variant contributes to tumor progression, classifying it as oncogenic.

Predictive, Oncogenic evidence:

Predictive: The study discusses the development of KRAS G12C inhibitors, such as sotorasib and adagrasib, and their promising results in treating metastatic NSCLC, indicating a correlation between the G12C variant and response to these therapies.

Oncogenic: The research focuses on KRAS G12C as a somatic variant that contributes to tumor development, particularly in the context of resistance mechanisms against targeted therapies, which is a hallmark of oncogenic behavior.

Diagnostic evidence:

Diagnostic: The study mentions that patients had "RAS and BRAFV600E wild-type tumours," indicating that the presence or absence of the BRAFV600E variant is used to classify the tumors in relation to their HER2 expression status. This suggests that BRAFV600E is relevant for defining the subtype of colorectal cancer in the context of this study.

Predictive, Diagnostic evidence:

Predictive: The study discusses the identification of biomarkers associated with responsiveness to targeted therapies, indicating that certain variants correlate with treatment response in ovarian cancer. This suggests a predictive relationship between the identified biomarkers and the effectiveness of the therapies tested.

Diagnostic: The mention of biomarkers associated with different subsets of patient-derived ovarian cancer xenografts implies that these variants can be used to classify or define specific disease characteristics or treatment eligibility. This aligns with the diagnostic evidence type as it relates to the identification of disease subtypes based on genetic markers.

Predictive, Oncogenic evidence:

Predictive: The study indicates that the FGFR2 EID, including the N173del variant, is associated with sensitivity to FGFR inhibitors, as evidenced by the partial responses observed in patients treated with Debio 1347. This suggests that the presence of this variant can predict therapeutic response to specific treatments targeting FGFR.

Oncogenic: The expression of the FGFR2 EID, which includes the N173del variant, resulted in oncogenic transformation in NIH3T3 cells, indicating that this variant contributes to tumor development and progression. This transformation demonstrates the variant's role in driving cancer biology.

Predictive, Diagnostic evidence:

Predictive: The study discusses the response rates to tazemetostat treatment in patients with EZH2 mutations, indicating that the presence of the EZH2 mutation correlates with a higher objective response rate (69% in the EZH2mut cohort compared to 35% in the EZH2WT cohort). This suggests that the EZH2 mutation is predictive of treatment response to the EZH2 inhibitor.

Diagnostic: The abstract mentions that patients were categorized by their EZH2 mutation status (mutant or wild-type), which indicates that the EZH2 mutation status is used to classify patients with follicular lymphoma. This classification is essential for determining eligibility for the study and treatment with tazemetostat.

Diagnostic, Prognostic evidence:

Diagnostic: The study aims to define the landscape of high-grade gliomas (HGGs) in adolescents and young adults (AYAs) and emphasizes the importance of molecular subgrouping for classification, indicating that specific variants like histone H3 mutations are associated with distinct clinicopathological profiles.

Prognostic: The results highlight that molecular subgrouping has major prognostic importance, suggesting that certain variants correlate with disease outcomes independent of therapy, as the WHO grade was found to have no prognostic value.

Diagnostic, Oncogenic evidence:

Diagnostic: The abstract states that "H3F3A mutations to be specific to GBM and highly prevalent in children and young adults," indicating that the K27M variant is used to classify and define a specific subtype of glioblastoma multiforme (GBM).

Oncogenic: The abstract mentions that the K27M mutation in H3F3A "led to amino acid substitutions at two critical positions within the histone tail," suggesting that this somatic variant contributes to tumor development or progression in glioblastoma.

Predictive, Diagnostic, Prognostic evidence:

Predictive: The study discusses the correlation between PD-L1 expression levels and overall survival (OS) rates in patients treated with avelumab versus docetaxel, indicating that higher PD-L1 expression is associated with improved treatment response. This aligns with the predictive evidence type as it relates to therapy response based on the variant's status.

Diagnostic: The abstract mentions that the primary endpoint was OS in patients with PD-L1+ tumors, which indicates that the presence of PD-L1 expression is used to classify and define a specific patient population for treatment. This supports the diagnostic evidence type as it relates to the identification of a disease subtype based on the variant.

Prognostic: The results highlight the 2-year OS rates for patients with PD-L1+ tumors, demonstrating that the variant correlates with disease outcome independent of therapy. This supports the prognostic evidence type as it discusses survival rates associated with the variant.

Diagnostic, Predisposing evidence:

Diagnostic: The study discusses the substitution of glutamine for arginine in the context of hereditary breast cancer, indicating that this alteration may be involved in the development of the disease. The presence of this variant in patients with bilateral breast cancer suggests its potential role as a biomarker for disease classification.

Predisposing: The variant is described as being present in the germline of patients with hereditary breast cancer, indicating that it confers an inherited risk for developing the disease. The identification of this alteration in patients with a familial history of breast cancer supports its classification as a predisposing variant.

Diagnostic evidence:

Diagnostic: The study discusses the association of initial CD4+ T cell counts of < 200/mm3 with the presence of underlying diseases or tuberculosis, indicating that this variant can be used to classify or define a patient's condition. This aligns with the definition of a diagnostic evidence type, as it relates to identifying disease subtypes based on specific lymphocyte counts.

Predictive, Oncogenic evidence:

Oncogenic: The study discusses how oncogenic fusions involving the NRG1 gene contribute to tumor development and progression, particularly through the activation of HER3 and downstream signaling pathways. The evidence is supported by the observation that seribantumab treatment inhibited growth in cancer cells harboring NRG1 fusions, indicating the role of these fusions in tumorigenesis.

Predictive: The abstract highlights that seribantumab, an anti-HER3 antibody, effectively inhibited the growth of cancer cells with NRG1 fusions, suggesting a correlation between the presence of these variants and sensitivity to this specific therapy. This indicates that NRG1 fusions can predict response to seribantumab treatment in affected cancers.

nan evidence:

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Diagnostic, Oncogenic evidence:

Diagnostic: The study discusses the role of gene fusions in cancer diagnosis and mentions that the CHOP Fusion panel provides genomic information useful for clinical management, indicating its use in defining or classifying disease.

Oncogenic: The abstract states that many fusions encode oncogenic drivers, suggesting that these variants contribute to tumor development or progression.

Oncogenic evidence:

Oncogenic: The study discusses how the MEF2D rearrangements, which include the D30C variant, lead to increased transcriptional activity and cellular transformation in vitro, indicating that this variant contributes to tumor development or progression.

nan evidence:

Missing abstract

nan evidence:

Missing abstract

Diagnostic, Oncogenic evidence:

Diagnostic: The abstract discusses the detection of pathogenic mosaic mutations in genes linked to vascular malformations, indicating that these mutations can be used to confirm the diagnosis of the condition. The mention of "clinicopathological classification" and the importance of molecular analysis suggests that the variant is associated with defining or confirming a disease.

Oncogenic: The abstract notes that the identified mutations, including those in PIK3CA and other genes, are pathogenic and contribute to vascular malformations, which implies a role in tumor development or progression. The context of somatic mosaic mutations further supports the classification of the variant as oncogenic.

Oncogenic evidence:

Oncogenic: The study identifies activating KRAS mutations, specifically KRASG12V, in tissue samples from patients with arteriovenous malformations, suggesting that this somatic variant contributes to tumor development through the activation of the MAPK-ERK signaling pathway in brain endothelial cells.

Oncogenic evidence:

Oncogenic: The study identifies that most vascular anomalies with overgrowth harbor postzygotic gain-of-function mutations in oncogenes, indicating that these somatic variants contribute to tumor development or progression. This is supported by the use of tumor genetic profiling to detect these variants, which are typically associated with cancer.

Oncogenic evidence:

Oncogenic: The variant c.159_173del is described as a small intragenic deletion identified in patients with arteriovenous malformations (AVMs), contributing to the allelic spectrum of variants in the RAS/MAPK pathway, which is known to be pathogenic and involved in tumor development. The context of its identification in affected tissue suggests a role in tumor progression related to AVMs.

Diagnostic, Oncogenic evidence:

Oncogenic: The study discusses that KRAS mutations, including p.G12D and p.G12V, are present in the majority of AVM specimens, indicating that these somatic mutations contribute to tumor development or progression in this context.

Diagnostic: The mention of KRAS mutations being linked to brain AVMs suggests that these variants can be used to classify or confirm the presence of this specific disease, thereby serving a diagnostic purpose.

Diagnostic, Oncogenic evidence:

Oncogenic: The study discusses that KRAS mutations, including p.G12D and p.G12V, are present in the AVM specimens and are described as "likely somatic disease-causing mutations," indicating their role in tumor development or progression.

Diagnostic: The mention of KRAS mutations being linked to brain AVMs suggests that these variants can be used to classify or confirm the presence of the disease, supporting their role as diagnostic markers.

Diagnostic, Oncogenic evidence:

Oncogenic: The study discusses that KRAS mutations, including p.G12D and p.G12V, are present in the AVM specimens and are described as "likely somatic disease-causing mutations," indicating their role in tumor development or progression.

Diagnostic: The mention of KRAS mutations being linked to brain AVMs suggests that these variants can be used to classify or confirm the presence of the disease, supporting their role as diagnostic markers.

nan evidence:

Missing abstract

Oncogenic evidence:

Oncogenic: The study identifies somatic mutations in PIK3CA that contribute to the development of CLOVES syndrome, indicating that these mutations play a role in tumor development or progression, as they are associated with increased phosphoinositide-3-kinase activity, which is a known oncogenic pathway.

Diagnostic, Oncogenic evidence:

Oncogenic: The study discusses that activating mutations of PIK3CA, including p.His1047Arg, function as oncogenes and are widely seen in human cancers, indicating that this variant contributes to tumor development or progression.

Diagnostic: The abstract mentions that the clinical and molecular spectrum of PIK3CA-related developmental disorders is correlated with types of mutations, suggesting that the presence of specific mutations like p.His1047Arg can be used to classify or define these disorders.

Diagnostic, Oncogenic evidence:

Diagnostic: The abstract discusses various diagnostic descriptors associated with PIK3CA mutations, indicating that these mutations are used to classify and define specific segmental overgrowth disorders. This aligns with the definition of the Diagnostic evidence type, as it highlights the association of the variant with distinct clinical phenotypes.

Oncogenic: The results section mentions somatic activating mutations in the growth-promoting serine/threonine kinase AKT1 and other signaling proteins in the RTK/PI3K/AKT/mTOR pathway, which contribute to tumor development in segmental overgrowth syndromes. This supports the Oncogenic evidence type, as it indicates that these mutations play a role in tumor progression.

Diagnostic evidence:

Diagnostic: The study discusses the detection of PIK3CA somatic alterations in the context of the PIK3CA-related overgrowth spectrum (PROS), indicating that these variants are used to classify and confirm the presence of this specific disease. The mention of a diagnostic yield of 71% further supports the role of these variants in defining the condition.

Diagnostic, Oncogenic, Functional evidence:

Diagnostic: The study identifies the cancer-associated p.His1047Leu mutation in PIK3CA in affected cells of a patient with a distinct overgrowth syndrome, suggesting that this variant is used to classify or define the disease.

Oncogenic: The presence of the p.His1047Leu and p.His1047Arg mutations in patients with overlapping syndromes indicates that these somatic variants contribute to tumor development or progression, as they are associated with a syndrome characterized by segmental overgrowth.

Functional: The study demonstrates that affected dermal fibroblasts with the identified mutations show enhanced basal and EGF-stimulated PIP3 generation, indicating that these variants alter molecular function and activate downstream signaling pathways.

Oncogenic evidence:

Oncogenic: The variant E542K is identified as a somatic mutation that contributes to the development of macrodactyly through the activation of the PI3K/AKT cell-signaling pathway, indicating its role in tumor development or progression.

Predictive, Oncogenic evidence:

Oncogenic: The study discusses the detection of the c.3140 A>T [p.H1047L] mutation in a biopsy from a patient, indicating that this somatic variant contributes to tumor development or progression in the context of the patient's condition.

Predictive: The abstract mentions that pharmacological blockade of the PI3K pathway resulted in a significant reduction of the proliferation rate, suggesting that targeting this pathway may be beneficial in future therapies for patients with mutations like those discussed, including the H1047L variant.

Diagnostic, Oncogenic evidence:

Diagnostic: The variant c.1633G>A, p.(Glu545Lys) is mentioned in the results section with its frequency across different cohorts, indicating its association with the disease context being studied. This suggests that the variant is being used to classify or define a specific disease or subtype.

Oncogenic: The presence of the variant c.1633G>A, p.(Glu545Lys) in the context of tumor development or progression is implied by its inclusion in a list of variants associated with a condition that involves overgrowth, which is often linked to oncogenic processes. This suggests that the variant may contribute to tumor development or progression.

Diagnostic, Oncogenic evidence:

Diagnostic: The study identifies a de novo mutation in AKT3 (p.Asn229Ser) as a rare cause of megalencephaly, indicating its role in defining or confirming the disease. This association with a specific condition supports the classification of the variant as diagnostic.

Oncogenic: The identification of mutations in AKT3, including p.Asn229Ser, suggests a contribution to tumor development or progression, particularly in the context of megalencephaly, which is associated with abnormal growth. This aligns with the oncogenic evidence type as it implies a role in disease pathology.

Predictive, Oncogenic evidence:

Oncogenic: The study discusses the TIE2-L914F variant as a common cause of venous malformations (VMs) and demonstrates that HUVECs expressing this mutation form VMs in a mouse model, indicating that the variant contributes to tumor development or progression.

Predictive: The results indicate that rapamycin effectively reduced mutant TIE2-induced AKT signaling and provided clinical improvement in patients, suggesting that the TIE2-L914F variant correlates with response to this therapy.

Diagnostic, Oncogenic evidence:

Oncogenic: The study identifies somatic mutations in the TEK gene, including Y897C and Y897H, in patients with vascular tumors and vascular malformations, indicating that these variants contribute to tumor development or progression in noninherited vascular anomalies.

Diagnostic: The presence of somatic mutations in the TEK gene, including Y897C and Y897H, is associated with specific subtypes of vascular anomalies, suggesting their role in the classification and diagnosis of these conditions.

Oncogenic, Functional evidence:

Oncogenic: The study identifies rare TEK variants that result in haploinsufficiency due to protein loss of function, indicating that these somatic variants contribute to the development of primary congenital glaucoma (PCG) by affecting anterior chamber vascular development and leading to elevated intraocular pressure.

Functional: The research demonstrates that individual TEK variants alter molecular function through mechanisms such as absence of normal protein production, protein aggregate formation, and altered subcellular localization, which directly impacts the protein's activity and stability.

Oncogenic, Functional evidence:

Oncogenic: The study discusses TIE2 mutations causing chronic activation of the MAPK pathway, which contributes to the loss of normal endothelial cell monolayer and is implicated in tumor development or progression. This indicates that the somatic variants in TIE2 play a role in the pathogenesis of venous malformations, aligning with oncogenic behavior.

Functional: The research demonstrates that TIE2 mutations result in defective receptor trafficking and altered subcellular localization, which affects the receptor's response to its ligand. This alteration in molecular function is indicative of the functional impact of the mutations on the TIE2 protein.

Predictive, Diagnostic, Prognostic, Oncogenic evidence:

Predictive: The study discusses the response rates to EGFR tyrosine kinase inhibitors (TKIs) among different mutation groups, indicating that the presence of the L858R mutation correlates with treatment response, as evidenced by the significantly different response rates between groups categorized by mutation type.

Diagnostic: The abstract mentions that the study investigates the clinical significance of various mutations, including L858R, in non-small cell lung cancer (NSCLC), suggesting that this variant is used to classify patients based on their mutation status.

Prognostic: The results indicate that patients with rare mutations, including those with L858R, had poorer progression-free survival compared to those with classical mutations, highlighting the variant's association with disease outcome independent of therapy.

Oncogenic: The L858R mutation is a well-known somatic mutation in the EGFR gene that contributes to tumor development in NSCLC, as implied by its classification as a classical mutation in the context of the study.

Predictive, Prognostic evidence:

Predictive: The study discusses the response to EGFR tyrosine kinase inhibitors (TKIs) in patients with the L858R mutation, indicating that patients with this mutation had a different time to progression on erlotinib compared to those with exon20 insertions. This suggests a correlation between the L858R variant and treatment response, which is characteristic of predictive evidence.

Prognostic: The median overall survival (OS) for patients with the L858R mutation was reported, providing information on disease outcome independent of therapy. This aligns with prognostic evidence as it correlates the variant with survival outcomes in lung adenocarcinoma patients.

Predictive, Oncogenic evidence:

Oncogenic: The abstract states that EGFR exon 20 insertions are "an oncogenic driver," indicating that these variants contribute to tumor development or progression in non-small cell lung cancer (NSCLC).

Predictive: The abstract mentions that EGFR exon 20 insertions are "associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs)," suggesting that the presence of this variant correlates with treatment response, specifically resistance to a class of therapies.

Predictive, Functional evidence:

Predictive: The study discusses how EGFR exon 20 mutations correlate with resistance to standard EGFR tyrosine kinase inhibitors (TKIs) and highlights the response rate of 64% in patients treated with poziotinib, indicating its effectiveness against these mutations. This suggests that the variant is predictive of treatment response to poziotinib, a specific therapy.

Functional: The abstract describes how the exon 20 mutations induce structural alterations that restrict the drug-binding pocket, affecting the binding of inhibitors. This indicates that the variant alters molecular function, specifically in relation to drug binding and inhibitor efficacy.

Predictive, Prognostic evidence:

Prognostic: The study reports a significant reduction in overall survival for patients with tumors harboring EGFR mutations at alanine 289, indicating that this variant correlates with disease outcome independent of therapy.

Predictive: The findings suggest that the EGFRA289V mutation may serve as a molecular marker for responsiveness to therapy with EGFR-targeting antibodies, indicating a correlation with treatment response.

Oncogenic, Functional evidence:

Oncogenic: The abstract discusses how somatic mutations in PIK3CA, including the variant c.1624G>A (p.Glu542Lys), contribute to the development of venous malformations (VMs) by causing chronic activation of AKT and dysregulation of angiogenic factors, indicating a role in tumor development or progression.

Functional: The abstract mentions that the PIK3CA mutations, including c.1624G>A, lead to abnormal endothelial cell morphology and that the p110alpha-specific inhibitor BYL719 can restore these abnormal phenotypes, suggesting that the variant alters molecular or biochemical function.

Oncogenic, Functional evidence:

Oncogenic: The abstract discusses how somatic mutations in PIK3CA, including the variant c.1624G>A (p.Glu542Lys), contribute to the development of venous malformations (VMs) by causing chronic activation of AKT and dysregulation of angiogenic factors, indicating a role in tumor development or progression.

Functional: The abstract mentions that the PIK3CA mutations, including c.1624G>A, lead to abnormal endothelial cell morphology and that the p110alpha-specific inhibitor BYL719 can restore these abnormal phenotypes, suggesting that the variant alters molecular or biochemical function.

Oncogenic, Functional evidence:

Oncogenic: The abstract indicates that the L914F variant is a somatic mutation in TIE2 that contributes to the development of sporadic venous malformations (VMs) by causing ligand-independent receptor hyperphosphorylation in vitro, which is a characteristic of oncogenic behavior.

Functional: The abstract describes how the L914F mutation leads to ligand-independent receptor hyperphosphorylation, indicating that this variant alters the molecular function of the TIE2 protein.

Predisposing, Functional evidence:

Predisposing: The R849W mutation is described as co-segregating with the disease phenotype in one of the families, indicating that it is inherited and contributes to the development of venous malformations, which aligns with the definition of a predisposing variant.

Functional: The study reports that the R849W mutation results in ligand-independent hyperphosphorylation of the Tie2 receptor, demonstrating that this variant alters the molecular function of the protein, which is characteristic of a functional evidence type.

Diagnostic, Functional evidence:

Diagnostic: The abstract states that the arginine-to-tryptophan substitution at position 849 in the TIE2 gene "segregates with dominantly inherited VM in two unrelated families," indicating that this variant is used to define or confirm the disease of venous malformations.

Functional: The study demonstrates that the mutation "results in increased activity of TIE2," which indicates that the variant alters the molecular function of the TIE2 protein, supporting its classification as a functional variant.

Predisposing, Functional evidence:

Predisposing: The abstract describes R849W as a germline substitution associated with autosomal dominantly inherited cutaneomucosal venous malformation (VMCM), indicating that this variant confers inherited risk for developing the disease.

Functional: The abstract states that the R849W mutation results in a fourfold increase in ligand-independent phosphorylation of the TIE2 receptor, demonstrating that this variant alters the molecular function of the protein.

Diagnostic, Oncogenic evidence:

Diagnostic: The abstract states that "germline substitutions in the endothelial cell tyrosine kinase receptor TIE2/TEK cause a rare inherited form of venous anomalies," indicating that the R849W variant is associated with a specific disease (mucocutaneous venous malformations, VMCM), thus serving as a diagnostic marker.

Oncogenic: The abstract mentions a "somatic 2nd hit causing loss-of-function of the receptor in a resected VMCM," which suggests that the somatic mutations, including the R849W variant, contribute to tumor development or progression in the context of venous malformations.

Oncogenic evidence:

Oncogenic: The abstract indicates that the somatic L914F TIE2 mutation is most often associated with unifocal venous malformations, suggesting that it contributes to tumor development or progression in this context. The mention of increased survival, invasion, and colony formation in endothelial cells further supports its role in oncogenesis.

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 abstract discusses sorafenib as a treatment for advanced thyroid cancer, specifically mentioning its ability to inhibit (V600E)BRAF, which indicates a correlation with response to therapy. The mention of clinical trials demonstrating the effectiveness of sorafenib in advanced thyroid cancer further supports this classification.

Oncogenic: The abstract refers to (V600E)BRAF as an oncogenic variant, indicating its role in tumor development and progression, particularly in the context of thyroid cancer. The discussion of sorafenib's ability to inhibit oncogenic RET mutants and (V600E)BRAF reinforces the notion that this variant contributes to cancer biology.

Oncogenic evidence:

Oncogenic: The abstract discusses the development of bilateral invasive sinonasal mucosal melanoma (SNMM) in a patient, highlighting the presence of an EML4-ALK fusion as a significant genetic variant associated with the progression of the disease. This indicates that the variant contributes to tumor development, fitting the criteria for oncogenic evidence.

Predictive, Prognostic evidence:

Predictive: The study discusses the therapeutic activity of everolimus, an mTORC1 inhibitor, in patients with tumors harboring TSC1/TSC2 or MTOR mutations, indicating a correlation between these mutations and response to therapy. The mention of "objective response rate (ORR)" and treatment with everolimus highlights the predictive nature of the variant's impact on treatment response.

Prognostic: The results include median overall survival (OS) and median progression-free survival, which are outcomes that correlate with the disease course independent of therapy. This suggests that the presence of TSC1/TSC2 or MTOR mutations may have prognostic implications for patients' survival.

Predisposing, Functional evidence:

Predisposing: The abstract discusses the clinical relevance of rare germline variants in the BRCA2 gene, indicating that these variants can confer inherited risk for developing cancer. The mention of "inherited alterations in BRCA2" supports the classification of the variant as predisposing.

Functional: The results section describes the use of a homology-directed DNA repair (HDR) assay to evaluate the functional impact of the variant c.8167G>C, indicating that the variant alters molecular function as it was assessed for its ability to influence HDR activity. The experimental setup and analysis of the variant's effect on cell viability and HDR scores provide evidence of its functional implications.

Predictive, Oncogenic evidence:

Predictive: The study indicates that KRAS mutations are associated with resistance to monotherapy and combination therapy with PARP inhibitors and immune checkpoint blockade, suggesting a correlation between the variant and therapeutic response. This aligns with the definition of predictive evidence, as it discusses how the presence of the KRAS mutation affects treatment outcomes.

Oncogenic: The abstract mentions that mutant KRAS tumors are associated with poor outcomes and describes the mechanisms by which KRAS mutations contribute to tumor behavior, such as decreased therapeutic sensitivity and the activation of pathways that promote tumor growth. This supports the classification of the variant as oncogenic, as it highlights its role in tumor development and progression.

Predictive, Oncogenic evidence:

Predictive: The study discusses the ROS1 G2032R mutation in the context of resistance to therapies such as crizotinib and lorlatinib, indicating that this variant is associated with treatment response and resistance mechanisms in ROS1+ NSCLC. The mention of developing next-generation inhibitors that target mutations like G2032R further supports its predictive nature regarding therapy efficacy.

Oncogenic: The G2032R variant is identified as a mutation that contributes to resistance in ROS1+ NSCLC, suggesting its role in tumor progression and development. The study's focus on mutations that mediate resistance implies that G2032R is involved in oncogenic processes within the context of cancer.

Predictive, Prognostic evidence:

Predictive: The study indicates that midostaurin combined with standard chemotherapy significantly improved outcomes in patients with FLT3-mutated acute myeloid leukemia (AML), suggesting a correlation between the FLT3 mutation and response to this specific therapy.

Prognostic: The results show that patients with specific genotypes (NPM1mut/FLT3-TKDmut or CBF-rearranged/FLT3-TKDmut) had significantly prolonged overall survival (OS), indicating that these mutations correlate with better disease outcomes independent of therapy.

Predisposing evidence:

Predisposing: The study discusses hereditary breast and ovarian cancer, indicating that the variant is related to inherited risk for developing these diseases, which aligns with the definition of a predisposing variant. The mention of "hereditary" suggests that the variant is germline in nature.

nan evidence:

Missing abstract

Functional evidence:

Functional: The study discusses the introduction of the c.1906G>C (p.Ala636Pro) variant through site-directed mutagenesis, indicating that the variant was specifically engineered to assess its functional impact on the MSH2 protein. This suggests that the variant's molecular or biochemical function is being evaluated, which aligns with the definition of functional evidence.

Predisposing evidence:

Predisposing: The study identifies rare germline loss-of-function variants in PTPN14 that confer substantial risks of basal cell carcinoma (BCC), indicating that these variants are inherited and contribute to an increased risk of developing this cancer. The mention of "germline" and the association with cancer risk supports this classification.

Predictive, Oncogenic evidence:

Predictive: The study demonstrates that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence after radiotherapy in localized non-small cell lung cancer (NSCLC), indicating a correlation with treatment response. The findings suggest that these mutations could facilitate treatment personalization, particularly in overcoming radioresistance.

Oncogenic: The abstract indicates that KEAP1 and NFE2L2 mutations are major molecular drivers of clinical radioresistance, suggesting that these somatic variants contribute to tumor progression and response to therapy. This aligns with the definition of oncogenic variants as those that drive tumor development or progression.

Predictive, Functional evidence:

Predictive: The study demonstrates that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence after radiotherapy in localized non-small cell lung cancer (NSCLC), indicating a correlation between these mutations and treatment response. The findings suggest that genotyping for these mutations could facilitate treatment personalization, highlighting their role in radioresistance.

Functional: The study functionally evaluates KEAP1/NFE2L2 mutations and shows that only pathogenic mutations are associated with radioresistance, indicating that these mutations alter the molecular response to radiotherapy. Additionally, the research suggests that glutaminase inhibition preferentially radiosensitizes KEAP1-mutant cells, further supporting the functional impact of these mutations on treatment outcomes.

Predictive, Diagnostic evidence:

Predictive: The study discusses the efficacy of fluzoparib, a PARP inhibitor, in patients with germline BRCA1/2-mutated recurrent ovarian cancer, indicating a correlation between the presence of these mutations and the response to the therapy, as evidenced by the reported objective response rates.

Diagnostic: The abstract explicitly mentions that the study enrolled patients with "germline BRCA1/2 mutation," indicating that these variants are used to classify and confirm a specific subtype of ovarian cancer, thus supporting their role as diagnostic markers.

Predictive, Diagnostic evidence:

Predictive: The study indicates that encorafenib plus cetuximab improved overall survival (OS), objective response rate (ORR), and progression-free survival in patients with BRAF V600E-mutant metastatic colorectal cancer, suggesting a correlation between the BRAF V600E variant and response to this specific therapy.

Diagnostic: The mention of "BRAF V600E-mutant metastatic colorectal cancer" implies that the presence of the BRAF V600E variant is used to classify and define a specific subtype of colorectal cancer, indicating its role as a biomarker for diagnosis.

Oncogenic evidence:

Oncogenic: The abstract discusses how mutations in the RAS genes, including substitutions at Gly12, lead to increased RAS signaling, which is a characteristic of somatic mutations contributing to tumor development. The results section further emphasizes that somatic mutations in RAS genes, particularly at hotspots like Gly12, are commonly associated with tumors, indicating their role in oncogenesis.

Predictive evidence:

Predictive: The abstract discusses how complete response rates (CRc) correlate with the use of FLT3 inhibitors (FLT3i) in FLT3-mutated acute myeloid leukemia (AML), indicating that the variant's presence influences treatment response. The mention of higher CRc rates with FLT3i-based combinations compared to single-agent therapy further supports the predictive nature of the variant in relation to therapy outcomes.

Predictive, Diagnostic evidence:

Predictive: The study discusses the effectiveness of FLT3 and IDH inhibitors in combination with cytotoxic chemotherapy (CCT) or low-intensity therapy (LIT), indicating that the presence of IDH mutations correlates with response rates to these therapies in patients with FLT3-ITD/IDH co-mutated acute myeloid leukemia (AML). The mention of complete remission (CR) rates in relation to specific treatments suggests a predictive relationship between the variants and treatment outcomes.

Diagnostic: The abstract indicates that IDH1 and IDH2 mutations are commonly found in patients with FLT3-ITD-mutated AML, suggesting that these mutations can be used to classify or define a specific subtype of the disease. The identification of patients with "double-mutated" AML highlights the role of these variants in diagnosing and understanding the disease context.

Predictive, Prognostic evidence:

Prognostic: The study reports that overall survival (OS) at 5 years was significantly different between FLT3/TKD mutant and wild-type patients, indicating that the presence of these mutations correlates with disease outcome. The odds ratio and statistical significance (P = .002) further support the prognostic value of FLT3/TKD mutations in acute myeloid leukemia (AML).

Predictive: The abstract mentions that the findings have implications for risk stratification and therapy, suggesting that FLT3/TKD mutations may influence treatment response or resistance in AML. This indicates a potential predictive role of the variant in relation to therapy outcomes.

Diagnostic, Oncogenic evidence:

Diagnostic: The study identifies various FLT3 mutations, including Asp835Tyr, and discusses their incidence in Thai AML patients, indicating that these mutations are associated with the disease. This suggests that the presence of such mutations can be used to classify or confirm the diagnosis of AML in this population.

Oncogenic: The mention of FLT3 mutations, including Asp835Tyr, in the context of acute myeloid leukemia (AML) implies that these mutations contribute to tumor development or progression, as FLT3 mutations are known to play a role in the pathogenesis of AML.

Predictive evidence:

Predictive: The study identifies KRAS mutations as being exclusively found in MEK inhibitor (MEKi)-sensitive cell lines and NRAS mutations as mostly present in MEKi-resistant cell lines, indicating a correlation between these variants and the response to MEK inhibitors. This suggests that these mutations can serve as predictive biomarkers for therapy response in low-grade serous ovarian carcinoma.

Predictive, Diagnostic evidence:

Predictive: The study discusses the efficacy of lorlatinib compared to crizotinib in treating advanced ALK-positive non-small-cell lung cancer (NSCLC), indicating that lorlatinib is associated with significantly longer progression-free survival and higher response rates, which correlates with treatment response.

Diagnostic: The abstract mentions that the study focuses on patients with advanced ALK-positive NSCLC, indicating that the presence of the ALK variant is used to classify and confirm the disease subtype.

Predictive evidence:

Predictive: The study demonstrates that loss of HDAC5 confers resistance to CDK4/6 inhibitors such as palbociclib in prostate and breast cancer cells, indicating a correlation between the variant and treatment response. This suggests that HDAC5 status can influence sensitivity to specific therapies, which is a key aspect of predictive evidence.

Predictive, Functional evidence:

Predictive: The study identifies ACTL6A overexpression as a novel cause for platinum resistance, indicating that high levels of ACTL6A are associated with chemoresistance to cisplatin treatment. This suggests a correlation between the variant and resistance to a specific therapy, which is a key aspect of predictive evidence.

Functional: The research demonstrates that overexpression of ACTL6A leads to increased repair of cisplatin-DNA adducts, indicating that the variant alters the molecular function related to DNA damage repair mechanisms. This alteration in function is supported by the findings that depletion of ACTL6A inhibits the repair of cisplatin-induced DNA lesions, further emphasizing its role in biochemical processes.

Predictive, Oncogenic evidence:

Predictive: The study discusses the sensitivity of BRCA2-null prostate cancer cells to SRC inhibitors and the potential for combination treatment with PARP inhibitors, indicating a correlation with treatment response. The mention of "higher sensitivity to SRC inhibitors" and "combination treatment...had a synergistic effect" supports the predictive nature of the variant in relation to therapy outcomes.

Oncogenic: The generation of BRCA2-null prostate cancer cells and the observation of increased SRC phosphorylation suggest that the BRCA2 variant contributes to tumor development or progression. The study's focus on the effects of this somatic variant in cancer cell lines indicates its oncogenic role.

Predictive, Oncogenic evidence:

Predictive: The study identifies genes that support enzalutamide resistance, indicating that the presence or absence of these variants correlates with the response to the therapy. Specifically, the knockdown of ACAT1, MAP3K11, and PSMD12 resulted in decreased cell survival in response to enzalutamide, demonstrating their role in influencing treatment outcomes.

Oncogenic: The findings suggest that the variants discussed contribute to tumor development or progression, as the loss of these genes resulted in decreased cell survival in castration-resistant prostate cancer cells. The association of MAP3K11 expression with Gleason grade and its role in promoting cell survival further supports its oncogenic potential.

Predictive, Oncogenic evidence:

Oncogenic: The study indicates that Intermedin (IMD) plays a significant role in glioma malignancy by increasing the invasive ability of glioma cells and promoting cell proliferation, suggesting that it contributes to tumor development and progression.

Predictive: The treatment with anti-IMD monoclonal antibodies not only inhibited tumor growth but also enhanced the antitumor activity of temozolomide, indicating that IMD is associated with response to therapy in glioblastoma.

Predictive, Oncogenic evidence:

Predictive: The study discusses how KIF15 contributes to enzalutamide resistance in prostate cancer, indicating that targeting KIF15 could enhance treatment efficacy. This suggests a correlation between the KIF15 variant and resistance to the therapy, which aligns with the predictive evidence type.

Oncogenic: The findings indicate that KIF15 plays a role in enabling prostate cancer cells to develop therapy resistance, suggesting that it contributes to tumor progression. This aligns with the oncogenic evidence type as it demonstrates the variant's involvement in cancer development.

Predictive, Oncogenic evidence:

Predictive: The study discusses the clinical benefit of inhibitors targeting the RAS/MAPK signaling pathway in KRAS-mutant tumors, indicating that the combination of AZD0364 and selumetinib enhances efficacy and leads to tumor regression, which correlates with treatment response. This suggests that the KRAS mutation is predictive of the response to this specific combination therapy.

Oncogenic: The abstract highlights that mutations in the KRAS gene contribute to tumor development and progression, as evidenced by the characterization of KRAS-mutant cell lines and xenograft models, demonstrating the oncogenic role of KRAS mutations in cancer.

Predictive, Diagnostic evidence:

Predictive: The study discusses how blocking progesterone signaling with the pharmacologic inhibitor mifepristone effectively suppressed high-grade serous carcinoma (HGSC) development and improved mouse survival, indicating a correlation with treatment response.

Diagnostic: The mention of targeting progesterone/PR signaling as a potential chemopreventive strategy particularly in high-risk populations of women carrying a deleterious mutation in the BRCA gene suggests an association with disease classification and risk assessment.

Diagnostic, Prognostic evidence:

Diagnostic: The study mentions that the TP53 (p. W146fs) gene mutation is associated with early relapse and adverse prognosis in high grade serous ovarian cancer (HGSOC), indicating its role in defining or classifying the disease.

Prognostic: The abstract states that the TP53 (p. W146fs) mutation is reported to be associated with adverse prognosis in HGSOC, which correlates with disease outcome independent of therapy.

Predictive, Oncogenic evidence:

Predictive: The study indicates that brigatinib has been found to have antitumor activity in patients with the G1202R variant, suggesting a correlation with response to this specific therapy. This aligns with the predictive evidence type as it discusses the variant's relationship to treatment efficacy.

Oncogenic: The mention of G1202R in the context of antitumor activity implies that this somatic variant contributes to tumor development or progression, which is characteristic of oncogenic evidence. The variant's presence in patients with advanced ALK-positive NSCLC suggests its role in the disease's pathology.

Diagnostic, Prognostic evidence:

Diagnostic: The abstract states that the internal tandem duplication (ITD) of the juxtamembrane domain of FLT3 is the most frequent mutation in human acute myeloid leukemia and is significantly associated with leukocytosis and a poor prognosis, indicating its role in defining and classifying the disease.

Prognostic: The abstract mentions that the FLT3 ITD mutation is significantly associated with a poor prognosis, which correlates the variant with disease outcome independent of therapy.

Predictive, Oncogenic evidence:

Predictive: The study indicates that the chimeric transcript RAD51AP1-DYRK4 enhances sensitivity to the MEK inhibitor trametinib, suggesting a correlation between the variant and response to this specific therapy. This is evidenced by the statement that RAD51AP1-DYRK4 "endows increased sensitivity to the MEK inhibitor trametinib."

Oncogenic: The ectopic expression of RAD51AP1-DYRK4 leads to increased cell motility and transendothelial migration, which are indicative of tumor progression and suggest that this variant contributes to oncogenic processes in luminal B breast tumors. The activation of MEK/ERK signaling further supports its role in tumor development.

Predictive, Prognostic evidence:

Predictive: The study indicates that MET expression is associated with the benefit of MET TKI therapy, as only cases with detectable MET expression responded to treatment. This suggests that MET expression can predict the response to MET TKIs in patients with MET exon 14-altered lung cancers.

Prognostic: The results show that cancers with a high H-score for MET expression had a significantly longer progression-free survival (PFS) compared to those with lower scores, indicating that MET expression levels correlate with disease outcome independent of therapy.

nan evidence:

Missing abstract

Predictive, Prognostic evidence:

Predictive: The study discusses that responses to FLT3 inhibitors occurred in 32% of patients with FLT3-ITD mutations, indicating a correlation between the presence of this variant and treatment response. The mention of resistance in relation to the emergence of new mutations further supports the predictive nature of the FLT3-ITD variant in the context of therapy.

Prognostic: The results indicate that patients with unchanged FLT3 mutations at progression had a median survival of 5 months, while those with undetectable mutations or combined mutations had a median survival of 7 months. This suggests that the presence and status of FLT3 mutations correlate with disease outcome, independent of therapy.

Functional evidence:

Functional: The study discusses the establishment of Ba/F3 cells expressing FLT3-ITD-F691L and FLT3-ITD-F691I mutations, indicating that these variants are being used to assess their molecular or biochemical function in the context of small molecule TKI inhibitors. This suggests that the variants alter the function of the FLT3 protein, which is a key aspect of the study's focus on their role in response to treatment.

Predictive, Oncogenic evidence:

Oncogenic: The variant BRAFV600E is mentioned in the context of its role as a mutationally activated oncogenic driver in PDAC, specifically highlighting its association with resistance mechanisms to MEK inhibition. This indicates that the variant contributes to tumor development or progression in pancreatic ductal adenocarcinoma.

Predictive: The study discusses the MEK inhibitor trametinib, which is approved for treating melanoma and NSCLC harboring BRAF-V600E mutations, indicating that the presence of this variant correlates with therapeutic response. This suggests that BRAFV600E may influence the effectiveness of specific therapies, thus providing predictive evidence.

Prognostic evidence:

Prognostic: The study identifies higher expression levels of GLS2 and NCF2 as being associated with poor prognosis in glioblastoma, indicating that these genes correlate with disease outcome independent of therapy.

Predictive, Oncogenic evidence:

Predictive: The study discusses the detection of the L1196Q and L1196M variants in the context of resistance to ALK tyrosine kinase inhibitors (TKIs), indicating that these mutations are associated with treatment failure and resistance mechanisms. This suggests a correlation between these variants and the response to therapy, which aligns with the predictive evidence type.

Oncogenic: The presence of the L1196Q and L1196M variants in patients with ALK-positive NSCLC after TKI treatment implies that these somatic mutations may contribute to tumor progression and resistance, supporting their role in oncogenesis. The context of their detection in tumor specimens further reinforces this classification.

Predictive, Diagnostic evidence:

Predictive: The study discusses the response to the MEK inhibitor selumetinib in children with progressive low-grade gliomas (LGGs), indicating that 20% of subjects had sustained partial responses, particularly among those with BRAF aberrations. This suggests a correlation between the presence of BRAF variants and the therapeutic response to selumetinib.

Diagnostic: The study mentions that BRAF aberrations were determined in tumor tissue, indicating that these variants are used to classify or confirm the presence of specific tumor characteristics in pediatric LGGs. This aligns with the use of BRAF mutations as biomarkers in the diagnosis of these tumors.

Predictive, Diagnostic evidence:

Predictive: The study discusses the response rates to olaparib in patients with somatic BRCA1/2 mutations and germline mutations in HR-related genes, indicating that these variants correlate with treatment response. The mention of objective response rates (ORR) for gPALB2 and sBRCA1/2 mutations supports the predictive nature of these variants in relation to therapy effectiveness.

Diagnostic: The abstract indicates that the study assesses patients with specific mutations (gBRCA1/2 and HR-related genes), which are used to classify and define the patient population eligible for olaparib treatment. This classification based on mutation status aligns with the diagnostic evidence type, as it involves identifying patients who harbor these specific genetic alterations.

Diagnostic, Prognostic evidence:

Prognostic: The study reports that KRAS-mutant patients harboring SMARCA4 mutations showed poorer clinical outcomes, including disease-free survival and overall survival, indicating that these mutations correlate with adverse disease outcomes independent of therapy.

Diagnostic: The abstract discusses the association of SMARCA4 mutations with survival outcomes in KRAS-mutant lung adenocarcinoma patients, suggesting that these mutations can be used to classify or define a specific clinical subgroup within this disease context.

Predictive, Prognostic evidence:

Predictive: The study investigates the combination of afatinib and cetuximab in patients with EGFR-mutant non-small-cell lung cancer (NSCLC) to determine if it improves progression-free survival (PFS) compared to afatinib alone, indicating a focus on treatment response and resistance.

Prognostic: The results report no improvement in overall survival between the treatment groups, which suggests that the variant's presence does not correlate with disease outcome independent of therapy.

Predictive, Oncogenic evidence:

Oncogenic: The study discusses the biallelic inactivation of the SMARCB1 gene as a common genetic feature in rhabdoid tumors, indicating that this somatic variant contributes to tumor development and progression. The evidence is supported by the observation that loss of SMARCB1 function leads to downregulation of tumor suppressor genes, which is characteristic of oncogenic behavior.

Predictive: The abstract mentions that the novel histone deacetylase inhibitor, OBP-801, shows efficacy against rhabdoid tumors by inducing apoptosis and inhibiting cell growth, suggesting a correlation between the SMARCB1 variant status and response to this specific therapy. This indicates that the variant may predict sensitivity to OBP-801 treatment in rhabdoid tumors.

Predictive, Functional evidence:

Functional: The variant H689A is described as "lacking methyltransferase activity," indicating that it alters the molecular function of the EZH2 protein. This suggests that the variant impacts the biochemical activity of EZH2, which is a key aspect of its role in cancer biology.

Predictive: The study discusses the effects of ebastine treatment on tumor growth and progression, indicating that the presence of the H689A variant influences the response to this therapy. The mention of enhanced progression-free survival in patient-derived xenograft models further supports the predictive nature of this variant in relation to treatment outcomes.

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.

Prognostic evidence:

Prognostic: The abstract states that GPX1 is an "independent prognostic factor" for predicting the "progression of malignancy in gliomas," indicating a correlation with disease outcome independent of therapy.