Functional evidence:

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

Predisposing evidence:

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

Predictive, Oncogenic evidence:

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

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

Predictive, Functional evidence:

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

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

Predictive, Diagnostic evidence:

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

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

Predictive, Diagnostic evidence:

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

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

Oncogenic evidence:

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

Predictive evidence:

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

Predictive, Diagnostic evidence:

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

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

Predictive, Prognostic evidence:

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

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

Diagnostic, Oncogenic evidence:

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

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

Predictive evidence:

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

Predictive, Diagnostic evidence:

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

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

Predictive evidence:

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

Predictive, Functional evidence:

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

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

Predictive, Oncogenic evidence:

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

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

Predictive, Oncogenic evidence:

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

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

Predictive, Oncogenic evidence:

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

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

Predictive, Oncogenic evidence:

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

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

Predictive, Oncogenic evidence:

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

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

Predictive, Diagnostic evidence:

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

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

Diagnostic, Prognostic evidence:

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

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

Predictive, Oncogenic evidence:

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

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

Diagnostic, Prognostic evidence:

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

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

Predictive, Oncogenic evidence:

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

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

Predictive, Prognostic evidence:

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

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

nan evidence:

Missing abstract

Predictive, Prognostic evidence:

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

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

Functional evidence:

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

Predictive, Oncogenic evidence:

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

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

Prognostic evidence:

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

Predictive, Oncogenic evidence:

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

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

Predictive, Diagnostic evidence:

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

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

Predictive, Diagnostic evidence:

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

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

Diagnostic, Prognostic evidence:

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

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

Predictive, Prognostic evidence:

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

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

Predictive, Oncogenic evidence:

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

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

Predictive, Functional evidence:

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

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

nan evidence:

There are no mentions of the variant in the abstract or results section provided. Therefore, no CIViC evidence types can be classified based on the information given.

Prognostic evidence:

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

nan evidence:

Missing abstract

Predictive, Oncogenic evidence:

Oncogenic: The G659fs variant is described as a C-terminal truncation mutant that is a loss-of-function mutation, which contributes to the impairment of RNF43 activity and enhances Wnt/beta-catenin signaling, indicating its role in tumor development or progression.

Predictive: The study indicates that the G659fs mutant compromises RNF43 activity and predicts response to upstream Wnt inhibitors, suggesting that this variant correlates with sensitivity to specific therapies in cancers without microsatellite instability.

Predictive, Diagnostic evidence:

Predictive: The study discusses the combination of osimertinib and ramucirumab in patients with T790M-positive EGFR-mutant non-small cell lung cancer, indicating that the presence of the T790M variant is associated with treatment response and resistance to therapies, which aligns with predictive evidence.

Diagnostic: The abstract mentions that the study enrolled patients with EGFR T790M-positive NSCLC, indicating that the T790M variant is used to classify and confirm a specific subtype of lung cancer, thus supporting its role as a diagnostic marker.

Predictive, Oncogenic evidence:

Oncogenic: The abstract mentions a "rare point mutation of FLT3-TKD" and a "novel mutation of WT1" that were detected recurrently throughout the course of the disease, indicating that these mutations contribute to tumor development or progression in the context of acute promyelocytic leukemia (APL).

Predictive: The abstract discusses the patient's response to "reinduction therapy with arsenic trioxide and all-trans retinoic acid combined with daunorubicin," suggesting that the identified mutations may correlate with the patient's response to this specific therapy.

Predictive, Prognostic evidence:

Prognostic: The study reports that the variant rs3786362 in TYMS is significantly associated with progression-free survival (PFS) in metastatic colorectal cancer (mCRC) patients, indicating its potential as a prognostic biomarker. The hazard ratio (HR = 1.43) suggests that this variant correlates with reduced PFS, which is a measure of disease outcome independent of therapy.

Predictive: The results indicate that rs3786362 is also associated with disease control rate (DCR) in mCRC patients, suggesting that this variant may predict response to treatment. The odds ratio (OR = 1.97) indicates a correlation with reduced DCR, further supporting its role in predicting treatment outcomes.

Oncogenic evidence:

Oncogenic: The study discusses the ACTB-GLI1 fusion gene, which is associated with the pericytoma tumor, indicating that this somatic variant contributes to tumor development. The presence of the fusion gene and its mapping to specific chromosomal rearrangements supports its role in oncogenesis.

Predictive, Diagnostic, Oncogenic evidence:

Predictive: The study discusses the EGFR T790M mutation in the context of osimertinib treatment, indicating that the presence of this mutation is associated with acquired resistance to the therapy. This suggests a correlation between the T790M variant and treatment response, making it predictive of resistance to osimertinib.

Diagnostic: The abstract mentions that patients were identified based on being T790M-positive, which indicates that the T790M mutation is used to classify patients with advanced NSCLC who have acquired resistance to prior EGFR tyrosine kinase inhibitors. This supports the use of T790M as a diagnostic marker for this specific patient population.

Oncogenic: The T790M mutation is described as a mechanism of resistance in the context of tumor progression and treatment failure, indicating its role in the oncogenic process of non-small cell lung cancer. This aligns with the definition of an oncogenic variant contributing to tumor development or progression.

Diagnostic, Oncogenic evidence:

Diagnostic: The study demonstrates that the presence of HPV DNA is associated with cervical lesions, indicating that HPV can be used to classify or confirm the presence of dysplastic lesions in the cervix. The identification of HPV DNA in biopsy specimens correlates with histologic abnormalities, supporting its role as a diagnostic marker for cervical dysplasia.

Oncogenic: The findings suggest that HPV, particularly HPV 16, is likely a major etiologic agent in the pathogenesis of cervical dysplasia, indicating that the presence of this somatic variant contributes to tumor development or progression in cervical tissues. The study highlights the association of HPV with severe cervical intraepithelial neoplasia, further supporting its oncogenic potential.

Diagnostic, Oncogenic evidence:

Oncogenic: The variant c.275_276insGGCC is mentioned as a mutation found in TP53, which is known to contribute to tumor development and progression. The study's focus on the presence of this variant in the context of colorectal carcinoma suggests its role in oncogenesis.

Diagnostic: The presence of the c.275_276insGGCC variant in TP53 is discussed in relation to the genetic profiling of quadruple-wt mCRC patients, indicating its potential use in defining or classifying the disease. This aligns with the diagnostic evidence type as it helps in identifying specific genetic alterations associated with the disease.

Predictive, Prognostic evidence:

Predictive: The study indicates that the PIK3CA mutation p.K944N promotes cell viability in the presence of cetuximab, suggesting a correlation with resistance to this therapy. This aligns with the evidence type as it discusses the variant's role in treatment response.

Prognostic: The results show that patients with PIK3CA or RAS mutations, including p.K944N, had a pronounced decrease in progression-free survival compared to those without mutations. This suggests that the variant correlates with disease outcome independent of therapy.

Oncogenic, Functional evidence:

Oncogenic: The study describes how PIK3CA mutations were assessed for their activity in promoting tumor growth and transformation, indicating that these somatic variants contribute to tumor development or progression.

Functional: The research highlights the functional assessment of PIK3CA variants through in vitro and in vivo assays, demonstrating that these variants alter molecular activities, such as the activation of PI3K signaling pathways.

Prognostic evidence:

Prognostic: The study indicates that patients with higher STC1 expression exhibited shorter overall survival times compared to those with lower STC1 expression, suggesting that STC1 may serve as a prognostic biomarker in glioma. This correlation with survival outcomes is independent of therapy context, aligning with the definition of prognostic evidence.

Prognostic evidence:

Prognostic: The study identifies STEAP2 and STEAP3 as prognosis-related genes in glioblastoma (GBM), indicating their correlation with disease outcomes such as survival, which is supported by the development of a prognostic nomogram that incorporates these genes along with other clinical factors.

Oncogenic evidence:

Oncogenic: The abstract discusses a case of a neonatal round-cell sarcoma associated with the YWHAE-NUTM2B fusion gene, indicating that this fusion contributes to tumor development in this specific context. The mention of the fusion transcript's association with sarcomas suggests its role in oncogenesis, particularly in the described case.

Predictive, Diagnostic evidence:

Predictive: The study discusses the efficacy of almonertinib in patients with the EGFR T790M mutation, indicating that this variant correlates with treatment response, as evidenced by the reported objective response rate and disease control rate among patients harboring the mutation.

Diagnostic: The abstract mentions that tumor biopsies were obtained for the determination of EGFR T790M status, suggesting that this variant is used to classify patients with locally advanced or metastatic NSCLC, thereby serving as a biomarker for the disease.

Predictive, Prognostic, Oncogenic evidence:

Prognostic: The abstract indicates that TLE2 expression is correlated with prognosis in patients with PDAC, suggesting its role in predicting disease outcomes such as survival or progression.

Predictive: The mention of "gemcitabine sensitivity" in the context of TLE2 suggests that this variant may influence the response to this specific therapy, indicating a predictive relationship.

Oncogenic: The abstract describes TLE2 as functioning as a tumor suppressor gene, which implies that alterations in this gene may contribute to tumor development or progression in PDAC.

Predictive evidence:

Predictive: The study discusses the use of IACS-13909, a SHP2 inhibitor, in overcoming resistance to osimertinib in EGFR-mutant NSCLC, indicating that the variant's presence correlates with resistance to therapy and the potential for response to a new treatment strategy. The mention of "tumor regression" and "suppressing signaling through the MAPK pathway" further supports the predictive nature of the evidence regarding treatment response.

Diagnostic evidence:

Diagnostic: The abstract discusses the characteristic gene rearrangements associated with infantile fibrosarcoma (IFS), indicating that the presence of specific genetic alterations, such as the ETV6 and NTRK3 rearrangements, is used to define and classify the disease. The mention of the variant c.1916dupA in the results section further supports its relevance in the context of genetic characterization of the tumor.

Diagnostic, Predisposing evidence:

Predisposing: The abstract clearly states that "germline pathogenic variants in the DICER1 gene are the underlying cause of the syndrome," indicating that these variants confer inherited risk for developing the associated tumors, which aligns with the definition of predisposing evidence.

Diagnostic: The mention of "DICER1 syndrome" being characterized by "a distinctive constellation of neoplastic and dysplastic lesions" suggests that the variants are used to define and classify this syndrome, supporting the diagnostic evidence type.

Predictive, Oncogenic evidence:

Predictive: The study indicates that PIK3CA-mutant colorectal cancers show preferential inhibition of growth with the glutaminase inhibitor CB-839, suggesting a correlation between the PIK3CA mutation and response to this therapy. Additionally, the exploratory analysis of a phase I clinical trial hints that PIK3CA-mutant patients may derive greater benefit from the treatment strategy compared to wild-type patients, further supporting the predictive nature of this variant in therapeutic response.

Oncogenic: The abstract describes PIK3CA as frequently mutated in human cancers and specifically notes that oncogenic mutations in PIK3CA contribute to the dependency of colorectal cancers on glutamine, indicating its role in tumor development and progression. This aligns with the definition of oncogenic variants that drive cancer behavior.

Predictive evidence:

Predictive: The abstract states that the MUC16 mutation is "associated with reported genomic factors associated with response to and improved outcomes for ICI treatment in solid tumors," indicating a correlation with treatment response. This suggests that the variant may help predict sensitivity to immunotherapy.

Functional evidence:

Functional: The study discusses how silencing of FGD5-AS1 alters the viability, migration, and invasion of GBM cells, indicating that the variant affects molecular or biochemical functions through the regulation of the miR-103a-3p/TPD52 axis.

Predictive, Oncogenic evidence:

Predictive: The abstract states that "overexpression of IL2RA... is associated with chemotherapy resistance and poor outcome in acute myeloid leukemia (AML)," indicating a correlation between the variant and treatment response, which supports its classification as predictive evidence.

Oncogenic: The study describes IL2RA as promoting "proliferation and cell-cycle activity" and being "required for leukemogenesis," demonstrating that the variant contributes to tumor development and progression, thus classifying it as oncogenic evidence.

Diagnostic, Prognostic evidence:

Prognostic: The study reports that patients with tumors carrying KAT6A and MYC amplifications had shorter progression-free survival (PFS) and overall survival (OS), indicating that these variants correlate with disease outcomes independent of therapy. The hazard ratios provided further support the prognostic significance of these amplifications in endometrial serous carcinoma.

Diagnostic: The abstract mentions that somatic copy number alterations (CNA) were identified in tumor samples, and specific amplifications of genes like KAT6A and MYC were associated with advanced disease stages. This suggests that these variants can be used to classify or define disease subtypes based on their presence in tumor samples.

Oncogenic, Functional evidence:

Functional: The study demonstrates that the K652E mutation fails to phosphorylate PLCgamma1 in TERT-NHUC cells, indicating that this variant alters the molecular function of the FGFR3 protein, specifically its signaling capabilities.

Oncogenic: The results suggest that the K652E mutation, along with other FGFR3 mutations, may contribute to tumor development in urothelial carcinomas, as it is associated with a conformational change that leads to constitutive auto-phosphorylation of the receptor, a characteristic of oncogenic mutations.

Predictive evidence:

Predictive: The study discusses how the T790M variant is associated with resistance to the EGFR TKI osimertinib, indicating that this variant correlates with treatment response and resistance, which is a key aspect of predictive evidence. The mention of "hypoxia-induced resistance to EGFR TKI" further supports this classification as it directly relates to therapy outcomes.

Predictive evidence:

Predictive: The study discusses TAS-119 as a selective inhibitor of Aurora kinase A that enhances the antitumor efficacy of paclitaxel and docetaxel, indicating a correlation with response to these therapies. The mention of enhanced cell growth inhibition and the optimized combination therapy regimen suggests that the variant's presence may influence treatment sensitivity.

Predictive, Diagnostic, Oncogenic evidence:

Oncogenic: The study discusses RET rearrangements as "an emerging targetable oncogenic fusion driver in NSCLC," indicating that these somatic variants contribute to tumor development or progression.

Predictive: The results show that "overall survival was prolonged in patients treated with a selective RET tyrosine kinase inhibitor versus untreated patients," demonstrating a correlation between the RET variant and response to therapy.

Diagnostic: The abstract mentions that "molecular testing for RET is not yet routine," which implies that the presence of RET rearrangements is used to define or classify a subtype of NSCLC.

Predisposing evidence:

Predisposing: The study identifies the Ashkenazi Jewish founder variant rs56009889 as being statistically significantly more frequent in cases of lung adenocarcinoma (LUAD) compared to controls, indicating that this germline variant confers an inherited risk for developing the disease. The mention of "germline" in the context of the variant supports its classification as predisposing.

Predictive, Diagnostic, Prognostic evidence:

Predictive: The study discusses the sensitivity of BRCA1 or BRCA2-mutated breast cancers to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum agents, indicating that the presence of these mutations correlates with a positive response to the therapy involving veliparib combined with carboplatin and paclitaxel. This is further supported by the reported improvement in progression-free survival in patients with these mutations receiving the treatment.

Diagnostic: The abstract explicitly mentions that patients with "germline BRCA1 or BRCA2 mutation-associated" breast cancer were included in the trial, indicating that these mutations are used to classify and confirm the disease subtype. This establishes the role of BRCA mutations as a biomarker for identifying patients eligible for the study.

Prognostic: The results indicate that the median progression-free survival was significantly longer in the veliparib group compared to the control group, suggesting that the presence of a germline BRCA mutation correlates with improved disease outcomes independent of therapy. This highlights the prognostic value of the BRCA mutations in the context of treatment response.

Predictive, Diagnostic, Oncogenic evidence:

Predictive: The study discusses the activity of the combination of dabrafenib and trametinib in patients with BRAFV600E-mutated biliary tract cancer, indicating a correlation with treatment response. This suggests that the BRAFV600E mutation is predictive of sensitivity to this specific therapy.

Diagnostic: The abstract mentions that routine testing for BRAFV600E mutations should be considered in patients with biliary tract cancer, indicating that this variant is used to classify or confirm the disease subtype. This supports the use of BRAFV600E as a diagnostic marker in this context.

Oncogenic: The presence of the BRAFV600E mutation is associated with biliary tract cancer, and the study focuses on the treatment of patients with this mutation, suggesting that it contributes to tumor development or progression. This aligns with the definition of an oncogenic variant.

Predictive, Prognostic evidence:

Predictive: The study indicates that high EGFR expression is associated with poor in vitro and in vivo response to DRD2 inhibitors, suggesting that the variant's expression level can predict treatment efficacy. Additionally, the inverse correlation between EGFR staining intensity and clinical response in patients treated with ONC201 further supports this predictive relationship.

Prognostic: The median overall survival for patients with high versus low EGFR staining (162 days vs. 373 days) demonstrates that EGFR expression levels correlate with disease outcome, independent of therapy, indicating a prognostic role for this variant in glioblastoma.

Predictive evidence:

Predictive: The abstract indicates that rucaparib has antitumor activity specifically in patients with a deleterious BRCA alteration, suggesting a correlation between the variant and response to this therapy. This aligns with the definition of predictive evidence, as it discusses treatment response in the context of a specific variant.

Predictive, Diagnostic evidence:

Predictive: The study discusses how multiple clinical-grade antiandrogens slowed the growth of and radiosensitized AR-positive GBM cell lines and patient-derived xenografts (PDXs), indicating a correlation between the androgen receptor (AR) expression and response to therapy. This suggests that AR expression may predict sensitivity to antiandrogen treatment in glioblastoma.

Diagnostic: The abstract mentions that nearly half of GBM cell lines, PDXs, and human tumors expressed AR, indicating that AR expression can be used to classify or define a subtype of glioblastoma, specifically AR-positive GBMs. This association with a specific characteristic of the tumors supports its use as a diagnostic marker.

Prognostic evidence:

Prognostic: The study indicates that increasing CtBP2 expression in lung adenocarcinoma (LUAD) is significantly correlated with patients' survival, suggesting that it serves as a prognostic marker for the disease. The Kaplan-Meier survival analyses performed in the study further support this correlation with specific statistical significance (P = .028).

Predictive, Diagnostic evidence:

Diagnostic: The abstract discusses the molecular profiling efforts that have advanced the understanding of biologically and clinically heterogeneous disease subgroups in medulloblastoma, indicating that these efforts are aimed at improving diagnostic interventions.

Predictive: The mention of "translational opportunities" and "improved diagnostic and therapeutic interventions" suggests that the insights gained from molecular characterization may correlate with response to therapies, indicating a predictive aspect of the variant in relation to treatment outcomes.

Predictive evidence:

Predictive: The abstract discusses brigatinib as an ALK inhibitor with superior efficacy and tolerability, indicating its potential as a first-line treatment for ALK-positive NSCLC, which suggests a correlation between the ALK variant and response to this therapy.

nan evidence:

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Predictive, Prognostic evidence:

Predictive: The study reports that alectinib significantly improved progression-free survival (PFS) compared to crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC), indicating a correlation between the variant and response to therapy. The mention of "significantly prolonged investigator-assessed PFS" supports the predictive nature of the variant in relation to treatment outcomes.

Prognostic: The abstract discusses overall survival (OS) data, noting that the 5-year OS rate was higher with alectinib compared to crizotinib, which suggests that the variant correlates with disease outcome independent of therapy. The mention of "median OS was not reached with alectinib" further emphasizes the prognostic implications of the variant in this context.

Predictive, Diagnostic evidence:

Predictive: The study discusses the antitumor activity of a DRD1 agonist in combination with temozolomide (TMZ), indicating that DRD1 activation correlates with a therapeutic response in glioblastoma (GBM) cells. The mention of a "synergistic therapeutic effect" suggests that the variant's role is predictive of treatment outcomes.

Diagnostic: The expression of DRD1 in human GBM tissues is associated with a good clinical outcome, which implies that it may be used to classify or define a subtype of GBM based on its expression levels. This association supports the use of DRD1 as a potential biomarker in diagnosing or characterizing GBM.

Predictive, Functional evidence:

Predictive: The study discusses the role of miR-320a in relation to cisplatin resistance in lung adenocarcinoma, indicating that the expression levels of this miRNA correlate with treatment response, specifically in the context of chemotherapy. The mention of "cisplatin resistance" directly relates to the predictive nature of the variant's impact on therapy response.

Functional: The study investigates the biological function of miR-320a and its target genes, suggesting that it alters molecular functions related to tumor progression and signaling pathways. This aligns with the functional evidence type as it focuses on the molecular and biochemical roles of the miRNA.

Diagnostic evidence:

Diagnostic: The study discusses the development of a tool for discovering disease-related biomarkers, which implies that the variants are being used to classify or define a disease at the miRNA-set level. This aligns with the definition of diagnostic evidence as it relates to identifying disease associations.

Predictive, Prognostic evidence:

Predictive: The study indicates that higher baseline levels of OPN, VCAM-1, and PDGF-AA may predict progression-free survival (PFS) benefit from regorafenib compared with placebo, suggesting a correlation between these biomarkers and treatment response. Additionally, VCAM-1 was identified as potentially predictive of overall survival (OS) benefit from regorafenib, further supporting its role in therapy response.

Prognostic: The results highlight that six markers were found to be prognostic for progression-free survival (PFS) and nine markers for overall survival (OS), indicating that these biomarkers correlate with disease outcomes independent of therapy. This suggests their potential utility in assessing prognosis for patients with metastatic colorectal cancer.

Diagnostic, Prognostic evidence:

Diagnostic: The abstract states that SPC25 is an "effective diagnostic and prognostic biomarker for HCC," indicating its role in classifying or confirming the disease.

Prognostic: The abstract mentions that SPC25 "independently predicted poor overall survival of patients with HCC," which correlates the variant with disease outcome independent of therapy.

Prognostic, Oncogenic evidence:

Prognostic: The abstract indicates that patients with cholangiocarcinoma (CCA) harboring mutant IDH1 have a better prognosis than those with wild-type IDH1, suggesting a correlation between the IDH1 mutation status and disease outcome. This aligns with the definition of prognostic evidence, as it discusses survival outcomes independent of therapy.

Oncogenic: The study discusses the role of TET1 in CCA progression, indicating that TET1 contributes to tumor development and malignancy in CCA cells. This suggests that TET1 is involved in oncogenic processes, supporting its classification as an oncogenic variant.

Diagnostic evidence:

Diagnostic: The abstract discusses the identification of a mutation in GNAQ (c.626A>c, p.Gln209Pro) in a patient with congenital hemangioma, indicating that this variant is used to classify and confirm the diagnosis of the vascular tumor. The mention of "utility of targeted genetic testing to elucidate the exact mutation and thus classification of vascular tumors" further supports its role in diagnosis.

Predictive evidence:

Predictive: The study discusses how loss of Man2a1 in cancer cells increases their sensitivity to T-cell-mediated killing and enhances response to anti-PD-L1 treatment, indicating a correlation with treatment response. Additionally, the mention of swainsonine synergizing with anti-PD-L1 treatment further supports the predictive nature of the variant in relation to therapy efficacy.

Predictive, Oncogenic evidence:

Predictive: The study identifies that FGFR/FGF alterations lead to resistance to ER-directed therapies, specifically fulvestrant, indicating a correlation with treatment response. The mention of reversing resistance with FGFR inhibitors and other targeted therapies further supports the predictive nature of these findings regarding therapy sensitivity.

Oncogenic: The alterations in the FGFR pathway, including FGFR1, FGFR2, and FGF3 amplifications or mutations, are described as contributing to the development of resistance in ER+ breast cancer, suggesting a role in tumor progression. The evidence of these alterations being enriched under selective pressure from ER-directed therapy indicates their oncogenic potential.

Predictive, Diagnostic evidence:

Predictive: The study discusses how high levels of ERBB2 mRNA are associated with better response and progression-free survival in patients treated with T-DM1, indicating that ERBB2 expression correlates with treatment response. This suggests that ERBB2 levels can be used to predict the efficacy of T-DM1 therapy in HER2-positive metastatic breast cancer.

Diagnostic: The abstract mentions that the study analyzed ERBB2 expression in various tumor samples and identified a subset of tumors as ERBB2-high, which implies that ERBB2 levels can be used to classify or define a specific subtype of breast cancer and potentially other cancer types. This classification supports the use of ERBB2 as a biomarker in clinical settings.

Diagnostic, Predisposing evidence:

Diagnostic: The study mentions that polymorphic variants in LUZP2, including rs7943454, are associated with late-onset Alzheimer's disease, indicating its role in defining or classifying a disease.

Predisposing: The association of rs7943454 with the onset risk of Alzheimer's disease suggests that this variant may confer inherited risk for developing the disease, which aligns with the definition of a predisposing variant.

Predictive, Diagnostic evidence:

Diagnostic: The variant BRCA1:c.185delAG is mentioned as a pathogenic mutation represented by multiple patients in the dataset, indicating its role in defining or classifying a disease subtype. This suggests that the variant is used to confirm the presence of a specific genetic alteration associated with the disease.

Predictive: The abstract discusses reversion mutations in BRCA1 or BRCA2 being associated with resistance to PARP inhibitors and platinum, which implies that the presence of certain mutations, including BRCA1:c.185delAG, may correlate with treatment response or resistance. This indicates a predictive relationship between the variant and therapeutic outcomes.

Predictive, Diagnostic, Prognostic evidence:

Diagnostic: The study identifies SMARCA4 mutations as common alterations in non-small cell lung cancer (NSCLC) and discusses their association with other genomic abnormalities, indicating their role in classifying the disease.

Prognostic: The results indicate that SMARCA4 alterations are associated with shorter overall survival in patients with metastatic NSCLC, highlighting their significance as independent predictors of poor prognosis.

Predictive: The study reports that treatment with immune checkpoint inhibitors (ICI) is associated with improved outcomes in patients with SMARCA4-mutant tumors, suggesting that these mutations may correlate with sensitivity to this specific therapy.

Diagnostic, Functional evidence:

Diagnostic: The study identifies the TP53 c.1000G>C;p.G334R variant as a mutation associated with Li-Fraumeni syndrome (LFS), indicating its role in defining and confirming this familial cancer syndrome. The mention of the variant being found predominantly in Ashkenazi Jewish individuals further supports its diagnostic relevance in this population.

Functional: The transient transfection of the p.G334R allele demonstrated a mild defect in colony suppression assays, indicating that this variant alters the molecular function of the p53 protein. Additionally, the study reports that the G334R-mutant protein shows thermal instability and defective transactivation of certain p53 target genes, further supporting its functional impact.

Oncogenic, Functional evidence:

Oncogenic: The abstract discusses how IL6/STAT3 signaling drives metastasis in ER+ breast cancer, indicating that this pathway contributes to tumor development and progression, which aligns with the definition of an oncogenic variant.

Functional: The study highlights that STAT3 hijacks a subset of ER enhancers to drive a distinct transcriptional program, suggesting that the variant alters molecular function, specifically in the context of transcriptional regulation.

Predictive, Oncogenic evidence:

Predictive: The study discusses how blockade of the NRG1/HER3 axis can re-sensitize prostate cancer models to antiandrogen therapy, indicating that the variant may correlate with resistance to this specific therapy.

Oncogenic: The evidence suggests that the cancer-associated fibroblasts and their secretion of NRG1 contribute to tumor progression by activating HER3 signaling in prostate cancer cells, which aligns with the definition of a somatic variant contributing to tumor development.

Predictive, Oncogenic evidence:

Oncogenic: The study discusses a MYC-miRNA-MXI1 feedback loop that regulates proliferation and tumorigenesis in glioma, indicating that the variant contributes to tumor development or progression.

Predictive: The abstract mentions that the ethyl ester form of meclofenamic acid (MA2) enhances the effect of the chemotherapy drug temozolomide on suppressing proliferation of glioma cells, suggesting a correlation between the variant and response to therapy.

Functional evidence:

Functional: The abstract indicates that miR-146a and miR-26a could counteract biological effects of CEACAM6, suggesting that these variants alter molecular or biochemical functions related to CEACAM6. This implies a role in modulating the activity or expression of this gene, which aligns with the definition of functional evidence.

Prognostic evidence:

Prognostic: The study indicates that elevated SERINC2 expression predicted shorter overall survival (OS) in low-grade glioma (LGG) patients, suggesting that SERINC2 expression may serve as a prognostic marker for this patient group. The Cox regression analysis further supports that SERINC2 is an independent factor in determining OS for LGG patients.

Predisposing evidence:

Predisposing: The abstract discusses an "inherited contribution to primary brain cancer" and mentions the identification of "candidate predisposition genes," indicating that the variant rs3198697 is associated with inherited risk for developing brain cancer. The context of linkage analysis in high-risk pedigrees further supports this classification.

Predictive, Prognostic evidence:

Prognostic: The study reports on overall survival (OS) in patients with EGFR-mutated NSCLC and leptomeningeal metastases, indicating that T790M mutational status does not significantly affect median OS (10.1 months vs. 9.0 months, p = 0.936). This suggests that the T790M variant's presence does not correlate with disease outcome in this context, which aligns with the definition of prognostic evidence.

Predictive: The abstract discusses the treatment response to osimertinib in patients with T790M mutational status, indicating that patients treated with osimertinib had a superior OS compared to those not treated, regardless of T790M status. This suggests that the T790M variant may not predict response to osimertinib, but the context of treatment response is still relevant, thus supporting the predictive classification.

Predictive, Oncogenic evidence:

Predictive: The study discusses how the combination of DNMTi guadecitabine and PARPi talazoparib enhances the efficacy of PARPi therapy, indicating a correlation with treatment response irrespective of BRCA mutation status. This suggests that the variant's presence or absence does not affect the sensitivity to the combined therapy, which is a predictive aspect of the variant's role in treatment outcomes.

Oncogenic: The results indicate that the combination treatment decreased xenograft tumor growth, which implies that the variant contributes to tumor development or progression in the context of breast and ovarian cancers. This aligns with the oncogenic evidence type as it demonstrates the variant's role in cancer biology.

Prognostic evidence:

Prognostic: The abstract states that "Overexpressed SNHG6 was significantly associated with poor prognosis in various cancers," indicating that the variant correlates with disease outcome independent of therapy. This suggests that SNHG6 levels can be used to evaluate prognosis in cancer patients.

Prognostic evidence:

Prognostic: The study indicates that high LPAR1 expression is correlated with favorable overall survival in prostate cancer, suggesting its role as a prognostic biomarker. This correlation with survival outcomes, independent of therapy, supports the classification as prognostic evidence.