Diagnostic, Predisposing evidence:

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

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

Diagnostic evidence:

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

Diagnostic, Predisposing evidence:

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

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

Functional evidence:

Functional: The study discusses how mutations at residues K13 and K289 alter the molecular function of PTEN by affecting its stability and localization, specifically through mechanisms of mono- and polyubiquitination. This indicates that the variant K13 directly influences the biochemical properties of the PTEN protein.

Predictive, Oncogenic evidence:

Predictive: The study discusses how mTORC1 pathway-activating mutations correlate with an exceptional response to treatment with rapalogs, indicating that these mutations can predict sensitivity to this specific therapy in certain cancer types.

Oncogenic: The abstract mentions that mTOR mutations enhance mTORC1 kinase activity and contribute to tumor growth in VHL-deficient cells, demonstrating that these somatic mutations play a role in tumor development and progression.

Predictive, Oncogenic evidence:

Oncogenic: The study provides evidence that the somatic mutation c.7280T>C (p.Leu2427Pro) in the MTOR gene contributes to tumor development and progression, as it induces hyperactivation of the mTOR kinase, which disrupts neuronal migration and leads to spontaneous seizures. This indicates that the variant plays a role in the pathogenesis of focal cortical dysplasia type II (FCDII).

Predictive: The findings suggest that inhibition of mTOR with rapamycin can suppress cytomegalic neurons and epileptic seizures, indicating that the variant may correlate with treatment response in patients with FCDII. This positions the mutation as a potential therapeutic target for managing intractable epilepsy associated with this condition.

Predictive, Oncogenic, Functional evidence:

Functional: The study discusses how mutations in the p53 gene alter its transactivation function, indicating that these variants can change molecular activity and gene regulation. The assessment of p53 mutants' ability to transactivate from various response elements demonstrates a direct link between the mutations and their functional consequences.

Oncogenic: The abstract mentions that mutations in p53, a tumor suppressor, could lead to dramatic phenotypic changes and diversification of cell responses to stress, suggesting that these somatic mutations contribute to tumor development and progression. The classification of p53 mutants as loss of function or retaining transactivation further supports their role in cancer biology.

Predictive: The findings imply that the functionality of specific p53 mutations could affect clinical behavior and outcome in the context of a neoadjuvant chemotherapy treatment trial, indicating a potential correlation between these variants and treatment response.

Predictive, Oncogenic evidence:

Predictive: The study discusses the L1196M mutation as a gatekeeper mutation that limits the durability of response to crizotinib and other ALK inhibitors, indicating its role in resistance to therapy. This suggests that the presence of the L1196M variant correlates with treatment resistance, which is a key aspect of predictive evidence.

Oncogenic: The abstract mentions that the L1196M mutation is a major resistance mechanism to ALK inhibitors, which implies that it contributes to tumor progression and development in the context of ALK+ NSCLC. This aligns with the definition of oncogenic evidence, as the mutation is associated with the cancer-driving behavior of ALK fusion proteins.

Predictive, Oncogenic evidence:

Predictive: The study discusses the potential role of the SHP2 inhibitor SHP099 in combination with molecular-targeted therapy, indicating that this combination may enhance treatment response in ALK/ROS1/EGFR-altered non-small cell lung cancer (NSCLC). The mention of "growth inhibition of cancer cells" suggests a correlation with treatment sensitivity, which aligns with predictive evidence.

Oncogenic: The abstract highlights the involvement of oncogene alterations in ALK/ROS1/EGFR in non-small cell lung cancer, suggesting that these variants contribute to tumor development or progression. The context of resistance to therapies targeting these oncogenes further supports the classification as oncogenic.

Predictive evidence:

Predictive: The study indicates that the combination of mirvetuximab soravtansine and bevacizumab may benefit women with recurrent ovarian cancer and high folate receptor alpha (FRalpha) expression, suggesting a correlation with treatment response. The mention of an objective response rate of 64% in patients with FRalpha-high tumors further supports this predictive evidence.

Predictive, Oncogenic evidence:

Predictive: The presence of the D835Y variant is discussed in the context of a patient receiving an experimental clinical trial with a FLT3 inhibitor, indicating a correlation with treatment response. The mention of achieving complete morphological remission suggests that the variant may influence sensitivity to the therapy.

Oncogenic: The D835Y variant is described as part of two small TKD mutated clones that were detected in the patient, indicating its potential role in tumor development or progression. The presence of this variant alongside the FLT3 ITD mutation suggests it may contribute to the malignancy in the context of Acute Myeloid Leukemia.

Oncogenic evidence:

Oncogenic: The study demonstrates that loss of STAG2 enhances the metastatic potential of Ewing sarcoma xenografts, indicating that STAG2 mutations contribute to tumor development and progression. This is further supported by the observation that the oncogenic genetic program driven by the fusion transcription factor EWS/FLI1 is highly perturbed in STAG2 knockout cells.

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.

Predictive, Diagnostic evidence:

Predictive: The study assesses the antitumor activity of pralsetinib, a selective RET inhibitor, in patients with RET fusion-positive NSCLC, indicating a correlation between the RET fusion variant and response to this specific therapy. The mention of overall response rates in patients receiving pralsetinib further supports the predictive nature of the variant in relation to treatment efficacy.

Diagnostic: The paper discusses RET fusion-positive NSCLC, indicating that the presence of the RET fusion variant is used to classify patients with this specific subtype of lung cancer. This classification is essential for determining eligibility for treatment with pralsetinib, thus highlighting the diagnostic role of the variant.

Oncogenic evidence:

Oncogenic: The study identifies the p.G34R mutation in H3F3A as a somatic mutation found in non-brainstem paediatric glioblastomas, indicating its potential role in tumor development or progression. The context of the study focuses on somatic mutations in pediatric diffuse intrinsic pontine gliomas, which supports the classification of this variant as oncogenic.

Diagnostic, Prognostic evidence:

Diagnostic: The study identifies BRAF V600E mutations as a biomarker in pediatric low-grade gliomas (PLGGs), indicating its role in classifying and stratifying these tumors into different risk groups based on their molecular characteristics.

Prognostic: The results show that BRAF V600E is associated with shorter progression-free survival (PFS) and overall survival (OS) in a subset of PLGGs, suggesting its significance in predicting disease outcomes.

Predictive, Prognostic, Oncogenic evidence:

Predictive: The study found that patients with MET amplification were resistant to immune checkpoint blockade (ICB) treatment, indicating a correlation between the MET variant and treatment response. This suggests that MET amplification can predict resistance to ICB therapy, which is crucial for tailoring treatment strategies.

Prognostic: The results indicated that patients with MET amplification had poor progression-free survival, demonstrating that this variant correlates with disease outcome independent of therapy. This highlights the potential of MET amplification as a prognostic marker in lung cancer.

Oncogenic: The study describes how oncogenic MET signaling contributes to tumor behavior by inducing phosphorylation of UPF1 and downregulating STING expression, which is indicative of its role in tumor development and progression. This evidence supports the classification of MET amplification as an oncogenic variant.

Predictive, Oncogenic evidence:

Predictive: The study discusses the therapeutic implications of KRAS mutations, particularly how MEK inhibition has minimal effect as a single agent for PDAC, indicating a relationship between the variant and treatment response. The combination of glucose metabolism inhibition and MEK inhibition shows potential for inducing apoptosis and prolonging overall survival, suggesting that KRAS mutations may influence sensitivity to this combined therapy.

Oncogenic: The abstract highlights the role of KRAS mutations, specifically KrasG12D, in tumor maintenance and progression in pancreatic ductal adenocarcinoma (PDAC), indicating that this somatic variant contributes to tumor development. The investigation into the pathways activated by KRAS mutations further supports its oncogenic role in PDAC.

Diagnostic, Functional evidence:

Diagnostic: The study identifies the presence of MAP2K1 (p.K57N) variants in the tissue adjacent to cartilage, indicating an association with the condition of arteriovenous malformation (AVM). This suggests that the variant is used to classify or confirm the disease state in the affected tissues.

Functional: The presence of the MAP2K1 (p.K57N) variant is shown to have different mutant allele frequencies in endothelial cells compared to non-endothelial cells, indicating that it alters the molecular or biochemical function within these cell types. This suggests a functional impact of the variant on the cellular behavior in the context of AVM.

Predictive, Oncogenic evidence:

Predictive: The study indicates that "depletion of SAMMSON sensitized mutant BRAF melanoma cells to RAF inhibitors in vitro and in vivo," suggesting that SAMMSON plays a role in the response of these cells to therapy, specifically RAF inhibitors. This aligns with the definition of predictive evidence, as it discusses the correlation between the variant and treatment sensitivity.

Oncogenic: The abstract states that "the long noncoding RNA (lncRNA) SAMMSON is required for human melanoma cell growth and survival," indicating that SAMMSON contributes to tumor development or progression in melanoma. This supports the classification as oncogenic, as it highlights the role of SAMMSON in cancer cell viability.

nan evidence:

There are no mentions of the variant in the abstract or results section that provide evidence for any of the CIViC evidence types. Therefore, no classifications can be made based on the provided text.

Predictive, Diagnostic evidence:

Predictive: The study discusses how pembrolizumab improved overall survival (OS) in patients with advanced NSCLC with PD-L1 tumor proportion score (TPS) >=50% and >=1%, indicating a correlation between the PD-L1 status and response to therapy. The hazard ratios provided for OS further support the predictive nature of the variant in relation to treatment outcomes.

Diagnostic: The mention of PD-L1 TPS as a criterion for patient selection in the study indicates its role in classifying patients for treatment, thus serving as a diagnostic marker for advanced NSCLC. The use of specific TPS thresholds to define patient eligibility for pembrolizumab treatment highlights its diagnostic significance.

Predictive, Oncogenic evidence:

Predictive: The study indicates that increased levels of DLL1 in the tumor microenvironment sensitize tumors to anti-CTLA4 treatment, resulting in tumor regression and prolonged survival, which suggests a correlation between DLL1 levels and response to therapy.

Oncogenic: The findings demonstrate that elevated DLL1 levels contribute to tumor vascular normalization and tumor growth inhibition, indicating a role in tumor development or progression within the context of the study.

Predictive, Diagnostic evidence:

Predictive: The study discusses the efficacy of apatinib plus gefitinib as first-line therapy in patients with EGFR-mutant NSCLC, specifically mentioning the L858R mutation as part of the inclusion criteria for treatment-naive patients. This indicates a correlation between the presence of the L858R variant and the response to the combination therapy, thus classifying it as predictive evidence.

Diagnostic: The abstract explicitly states that patients with the EGFR exon 21 L858R mutation were included in the study, indicating that this variant is used to classify and define a specific subtype of NSCLC. This supports the classification of the L858R variant as diagnostic evidence.

Oncogenic, Functional evidence:

Oncogenic: The study identifies the p.Tyr562Cys variant as a somatic variant that contributes to tumor development or progression, specifically in the context of fusiform cerebral aneurysms, as indicated by the presence of somatic-activating PDGFRB variants and their association with overactive auto-phosphorylation and downstream signaling activation.

Functional: The variant is shown to cause non-ligand-dependent auto-phosphorylation in PDGFRB, indicating that it alters the molecular function of the protein, which is supported by the findings of overactive phosphorylation and downstream activation of signaling pathways in patient cells harboring the variant.

Diagnostic, Oncogenic evidence:

Diagnostic: The abstract states that the mosaic PDGFRB c.1685A > G p.(Tyr562Cys) variant is associated with a specific phenotype, indicating its role in defining and classifying conditions related to PDGFRB-activating variants.

Oncogenic: The mention of segmental overgrowth and aneurysms due to the mosaic PDGFRB p.(Tyr562Cys) variant in the results suggests that this somatic variant contributes to tumor development or progression, particularly in the context of vascular malformations.

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 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 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 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.

Diagnostic, Predisposing evidence:

Predisposing: The abstract clearly states that "germline mutations in RASA1 are associated with capillary malformation-arteriovenous malformation (CM-AVM) syndrome," indicating that the c.1248T>G variant is inherited and confers risk for developing this syndrome.

Diagnostic: The mention of the c.1248T>G variant being tracked through the family and identified as a "familial germline heterozygous novel pathogenic RASA1 variant" supports its role in defining and confirming the diagnosis of CM-AVM syndrome.

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:

Parsing error: argument of type 'NoneType' is not iterable

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 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.