RESUMEN
PURPOSE: BRCA1 pathogenic variant heterozygotes are at a substantially increased risk for breast and ovarian cancer. The widespread uptake of testing has led to a significant increase in the detection of missense variants in BRCA1, the vast majority of which are variants of uncertain clinical significance (VUS), posing a challenge to genetic counseling. Here, we harness a wealth of functional data for thousands of variants to aid in variant classification. METHODS: We have collected, curated, and harmonized functional data for 2701 missense variants representing 24.5% of possible missense variants in BRCA1. Results were harmonized across studies by converting data into binary categorical variables (functional impact versus no functional impact). Using a panel of reference variants we identified a subset of assays with high sensitivity and specificity (≥80%) and apply the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant interpretation guidelines to assign evidence criteria for classification. RESULTS: Integration of data from validated assays provided ACMG/AMP evidence criteria in favor of pathogenicity for 297 variants or against pathogenicity for 2058 representing 96.2% of current VUS functionally assessed. We also explore discordant results and identify limitations in the approach. CONCLUSION: High quality functional data are available for BRCA1 missense variants and provide evidence for classification of 2355 VUS according to their pathogenicity.
Asunto(s)
Neoplasias de la Mama , Neoplasias Ováricas , Proteína BRCA1/genética , Neoplasias de la Mama/genética , Femenino , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Genómica , Humanos , Neoplasias Ováricas/genéticaRESUMEN
ABSTRACT The tracheal pulmonary route is used in diverse experimental models for the study of drugs, infectious agents, and diseases. In view of its importance and associated difficulties, the present article proposes to give research groups up-to-date information on techniques to access the tracheal pulmonary pathway of small rodents.
RESUMO As vias de acesso traqueopulmonar vêm sendo utilizadas em diversos modelos experimentais que estudam a ação de fármacos e agentes infecciosos, além de enfermidades. Tendo em vista a sua importância e as dificuldades associadas, o presente artigo de atualização propõe-se a dar ao pesquisador as informações necessárias para o emprego das técnicas de acesso traqueopulmonar em pequenos roedores.