Predictive, Oncogenic evidence:

Predictive: The study discusses the resistance mechanisms to the AKT inhibitor MK2206, indicating that the expression of AKT3 in resistant cells correlates with a loss of sensitivity to this therapy. This suggests that AKT3 plays a role in the response to treatment, making it predictive of resistance to AKT inhibitors.

Oncogenic: The upregulation of AKT3 in AKT inhibitor-resistant breast cancer cells suggests that it contributes to tumor progression and resistance mechanisms, indicating its role as an oncogenic driver in this context.

Predictive, Diagnostic evidence:

Predictive: The study evaluates the efficacy of dovitinib, an FGFR inhibitor, in patients with advanced SCC of the lung whose tumors demonstrated FGFR1 amplification, indicating that the variant correlates with response to a specific therapy. The mention of "overall response" and "disease control rate" further supports this classification as it directly relates to treatment outcomes.

Diagnostic: The study specifies that patients were enrolled based on their tumors demonstrating FGFR1 amplification of > 5 copies, which indicates that this variant is used to classify and confirm a specific subtype of lung cancer. This association with a defined characteristic of the disease supports the diagnostic classification.

Predictive, Oncogenic evidence:

Predictive: The study demonstrates that ATM-deficient MCL cell lines, such as Granta-519 and UPN2, are more sensitive to PARP-1 inhibition, indicating a correlation between the ATM variant status and response to therapy. Additionally, the use of the PARP-1 inhibitor olaparib significantly decreased tumor growth and increased overall survival in mice with ATM-deficient tumors, further supporting the predictive nature of this variant in therapeutic response.

Oncogenic: The characterization of ATM alterations in MCL and the observation that ATM-deficient cells exhibit defective DNA damage signaling and increased sensitivity to treatment suggest that these somatic variants contribute to tumor development and progression in this cancer type. The study's focus on the functional consequences of ATM mutations in the context of cancer supports the classification of these variants as oncogenic.

Oncogenic, Functional evidence:

Functional: The study describes how the CHEK2 mutation p.R474C alters the tertiary structure of the CHK2 protein by disrupting a salt bridge, indicating a change in molecular function. Additionally, the cell-based transfection analysis showed that this variant was unstable and scarcely activated, further supporting its functional impact.

Oncogenic: The conclusion that the homozygous CHEK2 variant p.R474C was contributory in the case of familial cancer suggests that this somatic variant may play a role in tumor development or progression, particularly given the context of multiple primary cancers in the patients.

Diagnostic evidence:

Diagnostic: The abstract discusses the updated recommendations for the diagnosis and management of acute myeloid leukemia (AML), which includes a revised version of the ELN genetic categories. This indicates that the variants are being used to classify or define the disease, aligning with the diagnostic evidence type.

Predictive, Functional evidence:

Predictive: The study indicates that the JAK1S703I mutation is sensitive to treatment with the JAK1/2 inhibitor, ruxolitinib, suggesting a correlation between this variant and therapeutic response. This is supported by the observation that the mutant PDX model showed sensitivity to the treatment, while other non-activating mutants did not.

Functional: The JAK1S703I mutation was shown to activate the JAK-STAT signaling pathway and drive cell proliferation in vitro, indicating that this variant alters molecular function. The introduction of this mutation into cell lines demonstrated its capability to enhance signaling in the absence of cytokine stimulation.

Predictive, Diagnostic evidence:

Predictive: The study assesses the ability of tumor genomic loss of heterozygosity (LOH) to predict response to rucaparib, indicating that LOH high status correlates with a better response to this PARP inhibitor in patients with ovarian carcinoma. This is supported by the findings that progression-free survival was significantly longer in the LOH high subgroup compared to the LOH low subgroup, demonstrating the predictive nature of the variant in relation to treatment outcomes.

Diagnostic: The classification of patients into homologous recombination deficiency subgroups based on tumor mutational analysis, including BRCA mutant and LOH high, indicates that these variants are used to define and classify the disease subtype. This classification is essential for determining the appropriate treatment strategy, thus supporting the diagnostic evidence type.

Predictive, Oncogenic evidence:

Predictive: The abstract discusses the ability of the L858R mutation to predict sensitivity to gefitinib, stating that it has been examined for its predictive capabilities in the context of treatment response. The mention of patients with the L858R mutation who did not respond to gefitinib further emphasizes the predictive nature of this variant regarding treatment resistance.

Oncogenic: The L858R mutation is described as a common somatic mutation in the EGFR gene associated with non-small-cell lung cancer (NSCLC), indicating its role in tumor development or progression. The context of the mutation being part of the EGFR gene, which is known to drive cancer, supports its classification as oncogenic.

Predisposing, Oncogenic evidence:

Predisposing: The abstract mentions that DDX41 mutations are identified as both germline and acquired somatic mutations in families with multiple cases of hematologic malignancies, indicating that these mutations confer inherited risk for developing diseases like myelodysplastic syndrome and acute myeloid leukemia.

Oncogenic: The abstract suggests that DDX41 acts as a tumor suppressor and discusses the identification of mutations in families with hematologic malignancies, implying that these somatic mutations contribute to tumor development or progression.

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Predisposing evidence:

Predisposing: The abstract states that the identified 700-kb tandem duplication at locus 14q32.13-q32.2 "increases the predisposition to myeloid malignancies," indicating that this variant is associated with an inherited risk for developing disease.

Predisposing, Oncogenic, Functional evidence:

Predisposing: The study describes a familial acute myeloid leukemia (AML) syndrome caused by germline mutations in the DDX41 gene, indicating that these mutations confer inherited risk for developing the disease.

Oncogenic: The abstract mentions that DDX41 is affected by somatic mutations in sporadic cases of myeloid neoplasms, suggesting that these mutations contribute to tumor development or progression.

Functional: The abstract states that DDX41 lesions caused altered pre-mRNA splicing and RNA processing, indicating that the variant affects molecular or biochemical function.

Oncogenic evidence:

Oncogenic: The variant N356fs is mentioned in the results section as a somatic mutation associated with T-ALL, indicating its contribution to tumor development or progression. The classification as "homo (LOH)" further supports its role in oncogenesis within the context of leukemia.

Diagnostic, Predisposing evidence:

Predisposing: The study discusses inherited mutations in ETV6, including the N385fs variant, which are associated with susceptibility to acute leukemia, indicating that these mutations confer inherited risk for developing the disease.

Diagnostic: The presence of the ETV6 N385fs mutation is used to classify and confirm the diagnosis of leukemia in the affected individuals, as it segregates with the disease in the studied kindreds.

Predisposing evidence:

Predisposing: The study discusses a "familial platelet disorder with propensity to myeloid malignancy," indicating that the germline heterozygous mutations in Runt-related transcription factor 1 confer inherited risk for developing myeloid malignancies. This aligns with the definition of a predisposing variant as it is explicitly described as germline and associated with an inherited condition.

Diagnostic, Functional evidence:

Diagnostic: The abstract mentions that "Platelet dysfunction suggestive of defective delta-granule release could be of values for the diagnosis of FPD/AML," indicating that the variant is used to define or confirm a disease, specifically in the context of autosomal dominant thrombocytopenia.

Functional: The results section describes various assays performed to investigate platelet function and delta-granule release, which implies that the variant affects molecular or biochemical functions related to platelet aggregation and granule release.

Diagnostic, Predisposing evidence:

Predisposing: The study discusses "inherited thrombocytopenias," indicating that the variants are germline and confer inherited risk for developing this disorder. The mention of "inherited or sustained thrombocytopenia of unknown etiology" supports the classification as predisposing.

Diagnostic: The identification of "pathogenic" or "likely pathogenic" variants in patients with thrombocytopenia suggests that these variants are used to confirm or classify the disease. The use of whole exome sequencing to elucidate potential pathogenic genetic variants further supports this classification.

Predisposing, Oncogenic evidence:

Predisposing: The abstract discusses "monoallelic RUNX1 germline mutations" found in families with familial platelet disorder (FPD), indicating that these inherited mutations confer a genetic predisposition to developing acute myeloid leukemia (AML).

Oncogenic: The identification of "a second RUNX1 alteration" in AML cases, including "acquired point mutations" and "duplication of the altered RUNX1 allele," suggests that these somatic changes contribute to tumor development and progression in the context of AML.

Diagnostic, Prognostic evidence:

Diagnostic: The study discusses GATA2 deficiency and its association with various diseases, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), indicating that the variant is used to classify and confirm these conditions. The identification of genotype-phenotype associations further supports its role as a diagnostic marker.

Prognostic: The abstract mentions that monocytopenia and lymphocytopenia correlate with the presence of disease, suggesting that the variant may have implications for disease outcomes independent of therapy. This correlation indicates a potential prognostic value of the GATA2 deficiency in predicting disease severity or progression.

Predisposing, Functional evidence:

Predisposing: The study identifies the p.Thr355del variant as a heritable mutation associated with familial myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), indicating that it confers inherited risk for developing these diseases.

Functional: The abstract mentions that the mutations, including p.Thr355del, affect transactivation of target genes, cellular differentiation, apoptosis, and global gene expression, demonstrating that this variant alters molecular or biochemical function.

Prognostic evidence:

Prognostic: The abstract indicates that KRAS G13D is associated with poor survival outcomes in mCRC patients, suggesting that this variant correlates with disease prognosis independent of therapy. The mention of "inferior PFS and OS" highlights its relevance in predicting patient outcomes.

Predictive, Diagnostic, Oncogenic evidence:

Predictive: The study discusses the patient's response to pembrolizumab, indicating that the hypermutated glioblastoma may be susceptible to checkpoint blockade therapy, which correlates with the variant's potential impact on treatment response. The mention of "an objective radiographic response" suggests a relationship between the variant and the effectiveness of the therapy.

Diagnostic: The abstract states that the patient has a "POLE germline alteration," which is used to define the hypermutated genotype of the glioblastoma, indicating that this variant is associated with a specific disease subtype. This classification supports the use of the variant as a biomarker for identifying patients with this particular tumor profile.

Oncogenic: The presence of a hypermutated genotype in the glioblastoma suggests that the variant contributes to tumor development or progression, as indicated by the tumor's characteristics and the context of the disease. The study implies that the POLE alteration plays a role in the tumor's aggressive behavior and its response to treatment.

Predictive, Diagnostic evidence:

Predictive: The study indicates that patients with TP53 mutations had a significantly higher response rate to decitabine therapy, with 100% of those with TP53 mutations achieving bone marrow blast clearance compared to only 41% of wild-type TP53 patients. This suggests that the presence of TP53 mutations correlates with a favorable clinical response to the treatment.

Diagnostic: The abstract mentions that TP53 mutations are associated with an unfavorable-risk cytogenetic profile, which is used to classify patients in terms of their risk for poor outcomes. This association supports the use of TP53 mutations as a biomarker for defining patient subtypes in AML and MDS.

Predictive, Oncogenic evidence:

Predictive: The study discusses how MET inhibitors suppressed tumor growth in xenograft models and reports a case where treatment with the targeted inhibitor crizotinib led to substantial tumor shrinkage, indicating a correlation between the MET fusion variant and response to therapy.

Oncogenic: The identification of MET fusions that activated MAPK signaling and induced aggressive glial tumors in vivo provides evidence that these somatic variants contribute to tumor development and progression in pediatric glioblastoma.

Predictive, Prognostic evidence:

Predictive: The study discusses TP53 and MDM2 alterations as being associated with cisplatin resistance, indicating that these variants may correlate with treatment response and resistance to chemotherapy. The mention of actionable alterations in cisplatin-resistant GCTs suggests potential sensitivity to targeted therapies, further supporting the predictive nature of these findings.

Prognostic: The abstract states that TP53 and MDM2 alterations predicted adverse prognosis independent of the IGCCCG model, indicating that these variants correlate with inferior outcomes such as increased risk of cancer-related death. This suggests that the presence of these alterations can provide prognostic information regarding disease outcome.

Predictive, Oncogenic evidence:

Oncogenic: The L768S mutation is described as contributing to tumor development, as it exhibited a significant increase in tyrosine kinase-specific activity and promoted rapid growth in xenograft experiments. This indicates that the mutation plays a role in the oncogenic process within HER2-negative breast cancer.

Predictive: The study discusses how the L768S mutation affects sensitivity to HER2-targeted therapies, indicating that it may correlate with treatment response. Specifically, the presence of this mutation in HER2-negative tumors suggests a potential for these tumors to benefit from targeted therapies, highlighting its predictive nature regarding treatment outcomes.

Predictive, Oncogenic evidence:

Predictive: The study discusses the antitumor activity of dabrafenib plus trametinib specifically in patients with BRAF(V600E)-mutant NSCLC, indicating a correlation between the presence of this variant and the response to the therapy. The mention of "BRAF inhibition has shown antitumour activity" supports the predictive nature of the evidence regarding treatment response.

Oncogenic: The abstract states that BRAF mutations, including V600E, act as oncogenic drivers in non-small cell lung cancer, which indicates that these variants contribute to tumor development or progression. This classification is supported by the context of the study focusing on a specific mutation known to drive cancer.

Predictive, Diagnostic evidence:

Predictive: The study discusses how CDK12 deficiency serves as a clinically relevant biomarker of PARP1/2 inhibitor sensitivity, indicating that the presence of this variant correlates with response to therapy. The mention of "sensitivity to PARP1/2 inhibition" directly links the variant to treatment outcomes, fulfilling the criteria for predictive evidence.

Diagnostic: The identification of CDK12 as a biomarker of PARP1/2 inhibitor sensitivity suggests its role in classifying patients who may benefit from this specific therapy, thus providing diagnostic evidence. The abstract states that CDK12 is one of the genes significantly mutated in high-grade serous ovarian cancer, further supporting its use in defining a disease subtype.

Diagnostic evidence:

Diagnostic: The study identifies 3' end deletions in the EPCAM gene as a novel cause of Lynch syndrome, indicating that these deletions are used to classify and confirm the diagnosis of this genetic condition. The mention of the frequency of EPCAM deletions in confirmed Lynch syndrome families further supports its role as a diagnostic marker.

Predisposing evidence:

Predisposing: The abstract describes familial platelet disorder with predisposition to acute myelogenous leukaemia (FPD/AML) as an autosomal dominant disorder, indicating that the variant confers inherited risk for developing the disease. The mention of "haploinsufficiency of CBFA2" causing a congenital platelet defect and predisposing individuals to leukaemia further supports this classification.

Predictive, Prognostic evidence:

Prognostic: The abstract states that "the circulating concentrations of C-X-C motif chemokine ligand 10 (CXCL10), Fms-related tyrosine kinase 3 ligand (FLT3LG), interferon gamma (IFNG), and C-C motif chemokine ligand 4 (CCL4) were significantly associated with overall survival in both cohorts," indicating that these biomarkers correlate with disease outcome independent of therapy.

Predictive: The conclusion mentions that "High circulating levels of CXCL10 and FLT3LG predicted worse survival for patients with OS," suggesting that these biomarkers may correlate with treatment response or resistance, which aligns with predictive evidence.

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Predictive, Diagnostic, Oncogenic evidence:

Predictive: The abstract states that BRAF inhibitors are the standard treatment for metastatic melanoma with BRAF V600 mutations, indicating a correlation between the presence of this variant and the response to therapy. Additionally, the results highlight improved survival outcomes with BRAF inhibitors in patients with BRAF mutations, further supporting the predictive nature of this evidence.

Diagnostic: The abstract mentions that all patients had BRAFV600E mutations, which implies that this variant is used to classify and confirm the presence of a specific subtype of melanoma. This association with a specific disease subtype qualifies the evidence as diagnostic.

Oncogenic: The results section discusses the prevalence of BRAF mutations in malignant melanoma, specifically noting that the BRAF V600E mutation is the most common. This indicates that the variant contributes to tumor development or progression, supporting its classification as oncogenic.

Predictive evidence:

Predictive: The study discusses the correlation between isocitrate dehydrogenase 1/2 mutations and the response to venetoclax treatment, indicating that these mutations may serve as predictive markers of response consistent with BCL2 dependence. This suggests that the presence of these mutations could influence the effectiveness of the therapy in patients with AML.

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Diagnostic, Prognostic evidence:

Diagnostic: The presence of the T790M mutation is used to define a clinical subset of patients with acquired resistance to EGFR TKIs, indicating its role in classifying disease progression and prognosis.

Prognostic: The study reports that patients with the T790M mutation have a significantly longer postprogression survival compared to those without the mutation, suggesting that T790M correlates with a more favorable disease outcome.

Predictive, Oncogenic evidence:

Predictive: The study discusses the emergence of imatinib-resistant clones in patients with metastatic gastrointestinal stromal tumors (GIST) and correlates this with disease progression, indicating that the presence of specific mutations in the KIT and PDGFRA kinases is associated with resistance to imatinib therapy.

Oncogenic: The identification of new activating kinase mutations in 80% of patients with progressive disease suggests that these somatic variants contribute to tumor development or progression in the context of GISTs.

Oncogenic evidence:

Oncogenic: The study discusses clonal chromosome aberrations involving 2p23 and the rearrangement of the ALK gene, suggesting that these alterations contribute to the development of inflammatory myofibroblastic tumors (IMT). This indicates that the variant plays a role in tumor progression, aligning with the definition of oncogenic evidence.

Predictive, Prognostic evidence:

Predictive: The study discusses how mutation scoring based on in vitro inhibitory concentration of TKI-mutation pairs can predict long-term clinical outcomes, indicating that the T315I variant has a low sensitivity to treatment, which correlates with response rates to therapy.

Prognostic: The results indicate that tumors with low and intermediate mutation scores, including those with the T315I variant, had worse event-free and overall survival rates compared to those with highly sensitive mutations, demonstrating a correlation with disease outcome independent of therapy.

Predisposing, Oncogenic evidence:

Predisposing: The study identifies germline mutations in the ALK gene as the main cause of familial neuroblastoma, indicating that these inherited mutations confer a risk for developing the disease.

Oncogenic: The abstract mentions that somatically acquired mutations in the ALK gene were predicted to be oncogenic drivers, as they resulted in constitutive phosphorylation and were linked to tumor growth.

Predictive evidence:

Predictive: The abstract states that EGFR gene mutations, including G719X, predict favorable responses to EGFR tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). This indicates a correlation between the presence of the G719X variant and the effectiveness of specific therapies, qualifying it as predictive evidence.

Predictive, Diagnostic evidence:

Predictive: The study discusses the efficacy of trastuzumab-DM1 (T-DM1) in patients with HER2-positive metastatic breast cancer, indicating that the response rates were higher among patients with confirmed HER2-positive tumors. This suggests a correlation between the HER2 variant status and the response to the therapy, classifying it as predictive evidence.

Diagnostic: The abstract mentions that the response rates were higher among patients with confirmed HER2-positive tumors, which implies that the HER2 status is used to classify and confirm the disease subtype (HER2-positive metastatic breast cancer). This supports the classification as diagnostic evidence.

Diagnostic evidence:

Diagnostic: The abstract discusses the identification of individuals at increased risk of hereditary cancer syndromes and presents criteria for cancer genetic consultation referral, indicating that the variant is used to classify or confirm a disease or subtype. This aligns with the definition of the Diagnostic evidence type, as it involves the use of specific criteria to identify individuals who may harbor genetic variants associated with cancer risk.

Oncogenic evidence:

Oncogenic: The abstract discusses somatic mutations of EGFR that are associated with "oncogene addiction," indicating that these mutations contribute to tumor development or progression. The mention of "oncogenic shock" further supports the idea that these mutations play a critical role in the cancer's response to treatment, which is characteristic of oncogenic variants.

Predictive, Oncogenic evidence:

Oncogenic: The study identifies rearrangements of the RET proto-oncogene, specifically the CCDC6-RET fusion, as potential driver mutations in lung adenocarcinoma, indicating that this somatic variant contributes to tumor development and progression. The evidence is supported by the demonstration of the biological relevance of the CCDC6-RET gene products in promoting cell growth and survival.

Predictive: The study evaluates the efficacy of RET inhibitors, such as vandetanib, in reducing cell viability and demonstrates that treatment with these inhibitors can effectively target the CCDC6-RET fusion, suggesting a correlation with response to therapy. This indicates that the presence of the RET fusion may predict sensitivity to RET-targeted treatments.

Predictive, Diagnostic, Oncogenic evidence:

Oncogenic: The study identifies RET rearrangements as rare oncogenic alterations in non-small-cell lung cancer (NSCLC), indicating that these variants contribute to tumor development or progression.

Predictive: The results demonstrate that vandetanib, a tyrosine kinase inhibitor, shows clinical antitumor activity in patients with advanced RET-rearranged NSCLC, suggesting that the presence of RET rearrangements correlates with response to this specific therapy.

Diagnostic: The study defines RET rearrangement as a new molecular subgroup of NSCLC, indicating its role in classifying patients for targeted therapy, which aligns with the criteria for diagnostic evidence.

Predictive evidence:

Predictive: The study reports that the response rate of 33% with dabrafenib in patients with advanced BRAF V600E-mutant lung cancers indicates a correlation between the BRAF V600E variant and sensitivity to this specific therapy. This suggests that the presence of the BRAF V600E variant can predict treatment response to BRAF inhibitors.

Predictive evidence:

Predictive: The study discusses the efficacy of the CDK4/6 inhibitor ribociclib in combination with letrozole, indicating that this treatment correlates with improved progression-free survival in patients with HR-positive, HER2-negative advanced breast cancer. This suggests a predictive relationship between the variant (in this case, the treatment regimen) and the response to therapy.

Predictive, Prognostic evidence:

Predictive: The study discusses how the variant rs9637468 is associated with overall survival (OS) in patients treated with gemcitabine, indicating that it may help predict response to this therapy in pancreatic cancer. The mention of "gemcitabine response" directly links the variant to treatment outcomes, fulfilling the criteria for predictive evidence.

Prognostic: The results indicate that rs9637468 is associated with overall survival (OS) of patients treated with gemcitabine, which correlates with disease outcome independent of therapy. This association with OS suggests that the variant may have prognostic implications for patients undergoing treatment.

Prognostic, Predisposing evidence:

Predisposing: The study discusses "familial CEBPA mutations" and indicates that these mutations are "germ-line," which confers an inherited risk for developing acute myeloid leukemia (AML). This aligns with the definition of predisposing evidence as it highlights the genetic basis of the disease in affected families.

Prognostic: The abstract mentions a "cumulative incidence of relapse in familial AML was 56% at 10 years" and "long-term overall survival (10-year overall survival, 67%)," indicating that the presence of CEBPA mutations correlates with disease outcomes independent of therapy. This supports the classification as prognostic evidence.

Diagnostic, Oncogenic evidence:

Diagnostic: The abstract states that mutations occurring exclusively at arginine-625 in SF3B1 are associated with low-grade uveal melanomas, indicating that these mutations can be used to classify a distinct molecular subset of the disease.

Oncogenic: The results section describes the identification of deleterious somatic variants in SF3B1, specifically noting that the p.R625C alteration was found in multiple tumor samples, suggesting its role in tumor development or progression in uveal melanoma.

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Predictive, Oncogenic evidence:

Predictive: The study discusses how alterations in the mTOR pathway, specifically a nonsense mutation in TSC2, correlate with sensitivity to everolimus, indicating that this variant may predict treatment response. The mention of resistance developing in a patient after an 18-month response further emphasizes the predictive nature of the variant in relation to therapy outcomes.

Oncogenic: The identification of a mutation in TSC2 as a negative regulator of mTOR suggests that this somatic variant contributes to tumor development or progression, particularly in the context of anaplastic thyroid carcinoma. The study implies that the mutation plays a role in the tumor's response to treatment, reinforcing its oncogenic potential.

Predictive evidence:

Predictive: The abstract states that mutations in the Bcr-Abl kinase domain may cause resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia patients, indicating a correlation between the variant and treatment response. This suggests that the presence of specific mutations can influence the effectiveness of therapy, which aligns with the predictive evidence type.

Predictive evidence:

Predictive: The abstract discusses how NPM1 mutations in acute myeloid leukemia (AML) are associated with sensitivity to arsenic trioxide (ATO) and the beneficial effects of combining ATO with all-trans retinoic acid (ATRA) in treatment, indicating a correlation with treatment response. The statement about NPM1 mutant downregulation by ATO/ATRA potentiating response to daunorubicin further supports this classification.

Predictive, Oncogenic evidence:

Predictive: The study discusses the sensitivity of non-small-cell lung cancer (NSCLC) harboring the ALK rearrangement to the ALK inhibitor ceritinib, indicating a correlation between the presence of the ALK variant and the response to therapy. The overall response rate of 58% among patients treated with ceritinib further supports this predictive evidence regarding treatment efficacy.

Oncogenic: The mention of ALK rearrangement in NSCLC suggests that this somatic variant contributes to tumor development or progression, as it is associated with the cancer type being studied. The context of resistance mutations in ALK also implies its role in oncogenesis within the framework of the disease.

Predictive evidence:

Predictive: The study discusses the objective response rate (ORR) of alectinib in patients with crizotinib-refractory ALK-positive NSCLC, indicating that the variant (ALK rearrangement) correlates with treatment response to alectinib, a specific therapy. The mention of ORR and progression-free survival highlights the predictive nature of the variant in relation to therapy outcomes.

Predictive, Diagnostic, Oncogenic evidence:

Predictive: The abstract discusses the occurrence of BCR-ABL mutations, including T315I, and their contribution to resistance to tyrosine kinase inhibitor therapy, indicating a correlation between the variant and treatment response. The mention of "imatinib-resistant" mutations suggests that T315I is associated with resistance to this specific therapy.

Diagnostic: The abstract notes the incidence of the T315I mutation in patients with varying Sokal scores, implying its role in classifying or defining a subset of patients with chronic myeloid leukemia based on mutation status. This association with specific patient characteristics supports its use as a diagnostic marker.

Oncogenic: The T315I mutation is mentioned in the context of patients progressing to accelerated phase/blast crisis, indicating that it contributes to tumor progression in chronic myeloid leukemia. This suggests that T315I has oncogenic properties, as it is associated with a more aggressive disease state.

Predictive, Diagnostic evidence:

Predictive: The study evaluates the response of patients with CML and ALL to the BCR-ABL tyrosine kinase inhibitor STI571, indicating that the presence of the BCR-ABL variant correlates with treatment response, as evidenced by the reported response rates in patients with myeloid and lymphoid blast crises.

Diagnostic: The abstract mentions that BCR-ABL is present in virtually all cases of chronic myeloid leukemia (CML) and in a significant percentage of acute lymphoblastic leukemia (ALL), suggesting its role in defining and confirming these diseases.

Predictive, Diagnostic evidence:

Predictive: The study evaluates the response of patients with chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) to the BCR-ABL tyrosine kinase inhibitor STI571, indicating a correlation between the presence of the BCR-ABL variant and treatment response. The results show that a significant percentage of patients experienced a response to the therapy, demonstrating the predictive nature of the variant in relation to treatment efficacy.

Diagnostic: The presence of the BCR-ABL variant is used to classify patients with CML and ALL, as it is noted to be present in virtually all cases of CML and in a significant percentage of ALL cases. This establishes the variant as a key biomarker for diagnosing these diseases.

Predictive, Oncogenic evidence:

Predictive: The study discusses the use of STI571, a specific inhibitor of the BCR-ABL tyrosine kinase, in treating patients with chronic myeloid leukemia (CML), indicating that the presence of the BCR-ABL variant correlates with response to this therapy. The results show significant antileukemic activity and complete hematologic responses in patients treated with doses of 300 mg or more, highlighting the variant's role in treatment sensitivity.

Oncogenic: The abstract mentions that BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia (CML), indicating that this somatic variant contributes to tumor development and progression in this disease context. The evidence of its transforming function supports its classification as oncogenic.

Predictive, Oncogenic evidence:

Predictive: The abstract discusses the response rates of various EGFR mutations, including L861Q, to EGFR-tyrosine kinase inhibitors (TKIs) like gefitinib and erlotinib, indicating that these mutations show moderate sensitivities to these therapies. This suggests a correlation between the presence of the L861Q variant and the effectiveness of specific treatments, which aligns with the predictive evidence type.

Oncogenic: The mention of somatic mutations in the EGFR gene, including L861Q, in the context of lung adenocarcinoma implies that these mutations contribute to tumor development or progression. This classification is supported by the context of the study focusing on mutations that are prevalent in cancer and their implications for targeted therapy.

Oncogenic, Functional evidence:

Functional: The study describes the use of a mouse embryonic stem cell-based functional assay to characterize BRCA2 variants, indicating that these variants alter molecular or biochemical function, such as their ability to rescue lethality in Brca2-deficient cells and their effect on sensitivity to DNA-damaging agents.

Oncogenic: The classification of the BRCA2 variants as pathogenic or non-pathogenic based on their effects on genomic integrity and homologous recombination suggests that these somatic variants contribute to tumor development or progression.

Predictive, Prognostic evidence:

Predictive: The study indicates that miR-34a significantly sensitized the anticancer effects of 5-fluorouracil (5-FU), suggesting that the variant correlates with response to this specific therapy in pancreatic ductal adenocarcinoma (PDAC) patients.

Prognostic: The loss of expression of miR-34a is associated with disease progression and poor prognosis in PDAC patients, indicating that this variant correlates with disease outcome independent of therapy.

Diagnostic, Predisposing evidence:

Diagnostic: The study discusses the identification of germline mutations in the STK11 gene that are associated with Peutz-Jeghers syndrome, indicating that these mutations can be used to define and confirm the diagnosis of this autosomal-dominant disorder.

Predisposing: The abstract explicitly states that the identified mutations in the STK11 gene are germline mutations, which confer inherited risk for developing Peutz-Jeghers syndrome, a condition characterized by an increased risk for various neoplasms.

Predisposing evidence:

Predisposing: The study discusses hereditary cancer syndromes and identifies truncating germline mutations in the LKB1 gene associated with Peutz-Jeghers syndrome, indicating that these mutations confer an inherited risk for developing the disease. The mention of "germline mutations" and the context of a hereditary syndrome supports this classification.

Predictive evidence:

Predictive: The G497W mutation in SMO is associated with resistance to vismodegib, as it interferes with drug binding, indicating that this variant correlates with treatment response. The abstract specifically mentions that the mutation contributes to primary resistance in a patient undergoing treatment with vismodegib.

Diagnostic evidence:

Diagnostic: The study establishes that HMGA2-LPP and LPP-HMGA2 fusion genes are specific to lipoma, while TLS-CHOP and EWS-CHOP are specific to liposarcoma, indicating their use in classifying these adipocytic tumors. This classification supports the notion that these fusion genes can be used as biomarkers for diagnosing specific tumor types.

Predictive, Functional evidence:

Predictive: The study discusses how PDK1 and SGK1 contribute to the resistance of PIK3CA-mutant cancer cells to PI3Kalpha inhibition, indicating that the variant's presence correlates with treatment response. This suggests that targeting these kinases can restore sensitivity to therapy, which aligns with predictive evidence.

Functional: The results mention measuring S6 phosphorylation as a readout of mTORC1 activity, indicating that the variant affects molecular function related to signaling pathways. This suggests that the variant alters biochemical activity, which is characteristic of functional evidence.

Predictive, Oncogenic evidence:

Predictive: The study evaluates gefitinib in patients with metastatic colorectal cancer and discusses clinical outcomes such as progression-free survival and response rates, indicating a focus on the relationship between the variant (in this case, the EGFR signaling pathway) and treatment response.

Oncogenic: The study analyzes tumor biopsies for activation of the EGFR signaling pathway, which is indicative of the variant's role in tumor development or progression, particularly in the context of evaluating gefitinib's efficacy.

Predictive, Diagnostic evidence:

Predictive: The study compares the efficacy of afatinib and gefitinib in treatment-naive patients with EGFR mutation-positive non-small-cell lung cancer, specifically mentioning the Leu858Arg variant. This indicates that the variant is associated with treatment response, making it predictive of therapy outcomes.

Diagnostic: The abstract states that patients with a common EGFR mutation, including Leu858Arg, were included in the study, suggesting that this variant is used to classify patients as having EGFR mutation-positive NSCLC. This supports its role as a diagnostic marker for the disease.

Predictive, Oncogenic evidence:

Predictive: The study indicates that the substitution of threonine with isoleucine in the Abl kinase domain is associated with resistance to the Abl tyrosine kinase inhibitor STI-571, suggesting that this variant correlates with treatment response. The phrase "sufficient to confer STI-571 resistance" directly links the variant to therapeutic implications.

Oncogenic: The evidence presented shows that the threonine to isoleucine substitution contributes to drug resistance, which is a critical aspect of tumor progression in the context of chronic myeloid leukemia. This variant's role in conferring resistance indicates its involvement in oncogenic processes.

Predictive, Oncogenic evidence:

Predictive: The study discusses how the addition of retinoic acid (RA) to chemotherapy may improve survival in patients with NPM1 mutations, indicating a correlation between the NPM1 variant and response to therapy. The mention of "proposed benefit of adding RA to chemotherapy in NPM1 mutant AMLs" supports this classification.

Oncogenic: The abstract states that NPM1 mutations contribute to the disorganization of promyelocytic leukemia (PML) nuclear bodies and lead to differentiation and apoptosis in AML, suggesting that the NPM1 variant plays a role in tumor development or progression. This aligns with the definition of oncogenic variants contributing to cancer biology.

Predictive, Oncogenic evidence:

Predictive: The study discusses how overexpression of CRIPTO1 in EGFR-mutated NSCLC cells leads to resistance against EGFR tyrosine kinase inhibitors (EGFR-TKIs) like erlotinib, indicating a correlation between the variant and treatment response. The mention of "erlotinib sensitivity" and "erlotinib resistance" directly relates to the predictive nature of the variant's impact on therapy outcomes.

Oncogenic: The evidence presented shows that CRIPTO1 contributes to the development of resistance in EGFR-mutated NSCLC cells, suggesting its role in tumor progression. The activation of SRC and induction of epithelial-to-mesenchymal transition (EMT) further supports the oncogenic behavior of the variant in the context of cancer development.

Predictive evidence:

Predictive: The abstract discusses the acquired resistance involving the BTK C481S mutation in the context of treatment with the BTK inhibitor ibrutinib, indicating that this variant is associated with resistance to therapy. This suggests that the presence of the C481S mutation may predict a lack of response to ibrutinib treatment in patients with mantle cell lymphoma.

Predictive, Diagnostic evidence:

Predictive: The abstract discusses the treatment of a patient with advanced colorectal cancer using trastuzumab based on the presence of the ERBB2 p.L755S mutation, indicating a correlation between the variant and the therapeutic approach, which aligns with predictive evidence regarding treatment response.

Diagnostic: The mention of the ERBB2 p.L755S mutation in the context of identifying genetic driver events in tumors suggests its role in classifying or defining the disease, supporting its classification as diagnostic evidence.

Predictive, Oncogenic evidence:

Predictive: The study discusses the effectiveness of the combination of selinexor and ibrutinib in CLL, particularly noting that it is effective in a cell line harboring the BTK C481S mutation, which suggests that this variant may influence treatment response and resistance to therapy.

Oncogenic: The mention of the BTK C481S mutation in the context of acquired resistance to ibrutinib indicates that this somatic variant contributes to tumor progression and the development of resistance mechanisms in CLL.

nan evidence:

Missing abstract

Predictive, Oncogenic evidence:

Predictive: The study discusses the response to targeted therapy in patients with FGFR2 fusions, indicating that these genetic alterations correlate with treatment response. The mention of the E384X variant as a negative regulator of EGFR suggests its potential relevance in therapeutic contexts, particularly in relation to treatment strategies targeting the EGFR pathway.

Oncogenic: The E384X variant is described as an SNV in ERRFI1, which is a negative regulator of EGFR, implying its role in tumor biology and potentially contributing to tumor development or progression. This suggests that the variant may have oncogenic implications, particularly in the context of cholangiocarcinoma.

nan evidence:

Missing abstract

Predictive, Diagnostic, Oncogenic evidence:

Predictive: The abstract mentions that NF1 mutant melanomas can be effectively treated with EGFR inhibitors, indicating a correlation between the variant and response to therapy.

Diagnostic: The results section describes the identification of mutational profiles in melanoma samples, specifically noting that C>T transitions are characteristic of cutaneous melanoma, which supports the use of this variant in defining the disease subtype.

Oncogenic: The results highlight that the C>T transitions are part of the mutational spectra associated with cutaneous melanoma, suggesting that these somatic variants contribute to tumor development or progression.

Diagnostic, Oncogenic evidence:

Diagnostic: The study mentions that six (4%) of the GBM tumors were IDH1 p.R132H-mutated, indicating that this variant is used to classify or confirm a specific subtype of the disease, which aligns with the definition of a diagnostic evidence type.

Oncogenic: The presence of the IDH1 p.R132H mutation in the tumors suggests that this somatic variant contributes to tumor development or progression, which is characteristic of oncogenic evidence.

nan evidence:

Based on the provided abstract and results section, there is no specific mention of any variants or their implications. Therefore, I cannot classify any evidence types as there are no relevant statements to support any of the CIViC evidence types.

Diagnostic, Functional evidence:

Diagnostic: The abstract discusses the improvement in the accuracy of diagnosis for diffuse gliomas, indicating that the study evaluates genetic/clinical correlations, which may include the variant C228T as part of the diagnostic criteria for glioma classification.

Functional: The results section mentions the mutational analysis of the TERT promoter, specifically referring to the C228T variant, which implies that this variant is being analyzed for its molecular characteristics, such as its role in the context of tumor genetics.

nan evidence:

Missing abstract

Predictive, Functional evidence:

Functional: The study discusses how the mispairing of guanine with thymine during DNA replication, specifically the O6-meG/T mismatch, alters the cellular response to temozolomide treatment by initiating futile cycles of the mismatch repair machinery, leading to DNA damage and cell death. This indicates a change in molecular function due to the variant's presence.

Predictive: The abstract mentions that promoter methylation-mediated silencing of MGMT is associated with increased sensitivity towards temozolomide, suggesting that the guanine-thymine mispairing impacts the response to this specific therapy. This correlation indicates a predictive relationship between the variant and treatment outcome.

nan evidence:

There is no information provided in the abstract or results section regarding the variant(s) mentioned in the paper. Therefore, I cannot classify any evidence types based on the given text.

Diagnostic, Oncogenic evidence:

Diagnostic: The study identifies a de novo pathogenic variant in ELOC (c.236A>G, p.Tyr79Cys) in a proband with VHL disease, suggesting that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease who do not have detectable VHL variants. This indicates the variant's role in classifying or confirming the disease.

Oncogenic: The p.Tyr79Cys substitution is described as a mutational hotspot in sporadic VHL-competent RCC and has been shown to mimic the effects of pVHL deficiency on hypoxic signaling, indicating its contribution to tumor development or progression. This supports the classification of the variant as oncogenic due to its association with cancer-related mechanisms.

Predictive, Oncogenic evidence:

Predictive: The study indicates that AR gene rearrangements in CRPC tumors are associated with resistance to endocrine therapies, specifically mentioning that cell lines with these rearrangements were resistant to the AR antagonist enzalutamide. This suggests a correlation between the variant and treatment response, classifying it as predictive evidence.

Oncogenic: The abstract describes AR gene rearrangements as contributing to the development and progression of CRPC, highlighting their role in promoting the expression of tumor-specific AR variants. This supports the classification of the variant as oncogenic due to its involvement in tumor development.

Predictive, Oncogenic evidence:

Predictive: The study indicates that AR gene rearrangements in CRPC tumors are associated with resistance to endocrine therapies, specifically mentioning that cell lines with these rearrangements were resistant to the AR antagonist enzalutamide. This suggests a correlation between the variant and treatment response, classifying it as predictive evidence.

Oncogenic: The abstract describes AR gene rearrangements as contributing to the development and progression of CRPC, highlighting their role in promoting the expression of tumor-specific AR variants. This supports the classification of the variant as oncogenic due to its involvement in tumor development.

Predictive, Oncogenic evidence:

Predictive: The study indicates that AR gene rearrangements in CRPC tumors are associated with resistance to endocrine therapies, specifically mentioning that cell lines with these rearrangements were resistant to the AR antagonist enzalutamide. This suggests a correlation between the variant and treatment response, classifying it as predictive evidence.

Oncogenic: The abstract states that AR gene rearrangements contribute to the development and progression of CRPC, highlighting their role in tumor-specific AR variant expression. This supports the classification of the variant as oncogenic due to its involvement in tumor development.

Oncogenic evidence:

Oncogenic: The study identifies the 1520C>A mutation (T507K) in the PTPN11 gene as contributing to tumor development, as evidenced by its ability to induce transformed foci in NIH3T3 cells and promote tumor formation in nude mice, indicating its role as an oncoprotein in solid tumors.

Diagnostic evidence:

Diagnostic: The study discusses the potential diagnostic utility of the TRPS1::PLAG1 fusion for determining tumor origin, indicating that this variant can help classify and identify the type of tumor present. The mention of recurrent gene fusions in CMTs and their association with specific histological features further supports its role in disease classification.

Oncogenic evidence:

Oncogenic: The study identifies structural rearrangements involving the PLAG1 gene in chondroid syringomas, specifically the formation of NDRG1-PLAG1 and TRPS1-PLAG1 fusion transcripts, which suggests that these somatic variants contribute to tumor development or progression.

Oncogenic evidence:

Oncogenic: The study identifies structural rearrangements involving the PLAG1 gene in chondroid syringomas, specifically the NDRG1-PLAG1 and TRPS1-PLAG1 fusion transcripts, indicating that these somatic variants contribute to tumor development. The presence of these fusion genes suggests a role in the oncogenic process associated with this type of tumor.

Predictive, Oncogenic evidence:

Predictive: The variant FGFR1 p.V561M is described as imparting resistance to FGFR inhibitors, indicating its role in predicting treatment response and resistance to therapy in the context of pilomyxoid astrocytomas.

Oncogenic: The study identifies the FGFR1 p.V561M variant as a gatekeeper mutation that contributes to tumor development by imparting resistance to inhibitors, suggesting its role in the oncogenic process of pilomyxoid astrocytomas.

Predictive, Oncogenic evidence:

Predictive: The variant FGFR1 p.V561M is described as imparting resistance to FGFR inhibitors, indicating its role in predicting treatment response and resistance in the context of therapy for pilomyxoid astrocytomas.

Oncogenic: The study identifies the FGFR1 p.V561M variant as a gatekeeper mutation that contributes to the tumor's characteristics, suggesting its involvement in tumor development or progression.

nan evidence:

Missing abstract

Predictive, Diagnostic evidence:

Diagnostic: The study discusses the use of FISH analysis for screening ABL1 fusions in pediatric acute lymphoblastic leukemia (ALL), indicating that the presence of the NUP214-ABL1 fusion can be used to classify or confirm the disease. This suggests that the variant is associated with a specific subtype of leukemia, fulfilling the criteria for diagnostic evidence.

Predictive: The abstract mentions that ABL1 fusions are potentially targetable by kinase inhibitors, indicating a correlation between the presence of this variant and the response to specific therapies. This aligns with predictive evidence as it suggests that the variant may influence treatment options.

Functional evidence:

Functional: The variant p.Ser695Leu in EZH2 is mentioned in the context of sequencing results, indicating that it is a mutation found in the patient. This suggests that the variant may alter the molecular function of the EZH2 protein, which is relevant to its role in cancer biology.

nan evidence:

Missing abstract

Oncogenic evidence:

Oncogenic: The study discusses the mechanism by which SRA737 and PARPi synergistically inhibit tumor cell growth, indicating that the variant S3C is involved in tumor development or progression, particularly in the context of PARPi-resistant cell lines. This suggests that the variant contributes to the oncogenic processes in these cancer cells.

Predictive, Diagnostic evidence:

Predictive: The study discusses the addition of pembrolizumab to chemotherapy and its impact on disease-free survival (DFS) in patients with dMMR endometrial cancer, indicating a correlation between the dMMR phenotype and treatment response. The results show a significant hazard ratio for DFS in the dMMR population, suggesting that the variant's presence may predict a better response to the therapy.

Diagnostic: The abstract mentions the classification of patients based on their dMMR status, which is used to define a specific subtype of endometrial cancer. This indicates that the dMMR variant is associated with a particular disease phenotype, supporting its role as a diagnostic marker.

Predictive, Prognostic evidence:

Predictive: The study reports that patients with dMMR/MSI-H endometrial cancer treated with dostarlimab plus carboplatin-paclitaxel had a statistically significant reduction in the risk of death, indicating that the variant correlates with response to this specific therapy. The mention of hazard ratios and the context of treatment response supports this classification.

Prognostic: The results indicate a statistically significant overall survival benefit in patients treated with dostarlimab, with a specific hazard ratio reported for the dMMR/MSI-H population, suggesting that the variant correlates with disease outcome independent of therapy. This aligns with the definition of prognostic evidence.