ABSTRACT
MOTIVATION: Germline variant classification allows accurate genetic diagnosis and risk assessment. However, it is a tedious iterative process integrating information from several sources and types of evidence. It should follow gene-specific (if available) or general updated international guidelines. Thus, it is the main burden of the incorporation of next-generation sequencing into the clinical setting. RESULTS: We created the vaRiants in HC (vaRHC) R package to assist the process of variant classification in hereditary cancer by: (i) collecting information from diverse databases; (ii) assigning or denying different types of evidence according to updated American College of Molecular Genetics and Genomics/Association of Molecular Pathologist gene-specific criteria for ATM, CDH1, CHEK2, MLH1, MSH2, MSH6, PMS2, PTEN, and TP53 and general criteria for other genes; (iii) providing an automated classification of variants using a Bayesian metastructure and considering CanVIG-UK recommendations; and (iv) optionally printing the output to an .xlsx file. A validation using 659 classified variants demonstrated the robustness of vaRHC, presenting a better criteria assignment than Cancer SIGVAR, an available similar tool. AVAILABILITY AND IMPLEMENTATION: The source code can be consulted in the GitHub repository (https://github.com/emunte/vaRHC) Additionally, it will be submitted to CRAN soon.
Subject(s)
Genetic Variation , Neoplasms , Humans , United States , Genetic Testing , Genetic Predisposition to Disease , Bayes Theorem , Genome, Human , Neoplasms/genetics , AutomationABSTRACT
Defects in DNA repair genes have been extensively associated with cancer susceptibility. Germline pathogenic variants (GPV) in genes involved in homologous recombination repair pathways predispose to cancers arising mainly in the breast and ovary, but also other tissues. The RAD51 paralogs RAD51C and RAD51D were included in this group 10 years ago when germline variants were associated with non-BRCA1/2 familial ovarian cancer. Here, we have reviewed the landscape of RAD51C and RAD51D germline variants in cancer reported in the literature during the last decade, integrating this list with variants identified by in-house patient screening. A comprehensive catalog of 341 variants that have been classified applying ACMG/AMP criteria has been generated pinpointing the existence of recurrent variants in both genes. Recurrent variants have been extensively discussed compiling data on population frequencies and functional characterization if available, highlighting variants that have not been fully characterized yet to properly establish their pathogenicity. Finally, we have complemented this data with relevant information regarding the conservation of mutated residues among RAD51 paralogs and modeling of putative hotspot areas, which contributes to generating an exhaustive update on these two cancer predisposition genes.
Subject(s)
DNA-Binding Proteins , Genetic Predisposition to Disease , Ovarian Neoplasms , DNA-Binding Proteins/genetics , Female , Germ Cells , Germ-Line Mutation/genetics , Humans , Ovarian Neoplasms/geneticsABSTRACT
Sendo o medicamento genérico intercambiável com o medicamento de referência ambos devem apresentar a mesma segurança e eficácia que deverão ser comprovadas por ensaios que controlam sua qualidade durante todas as etapas que vão desde a sua concepção até a entrega ao paciente. Ensaios de biodisponibilidade e bioequivalência dos medicamentos genéricos são fundamentais e obrigatórios para a garantia da qualidade desses
