Reclassificação de variantes de sentido trocado no gene BRCA1 associadas ao câncer de mama e ovário hereditários

Germline pathogenic variants in BRCA1 and BRCA2 are the main cause of hereditary breast and ovarian cancer syndrome (HBOC). Affected individuals tend to develop cancer at an earlier age, more frequently breast and/or ovarian tumors before the age of 50. Therefore, an accurate classification of BRCA1/2 variants is critical in molecular diagnosis, leading to a precise clinical management and genetic counseling. Although some advances were made in the functional characterization of BRCA1 single nucleotide variants, there are still many variants classified as variants of unknown significance (VUS). Here we set out to reclassify BRCA1 missense variants by using functional data and comparing the resulting classification to the one encountered in the ClinVar database. As a result, 318 BRCA1 missense variants in critical functional domains of the protein were analyzed according to ACMG-AMP and Sherloc variant classification guidelines. A total of 85 (27%) variants using ACMG-AMP and 32 (10%) based on Sherloc were reclassified either as likely pathogenic or pathogenic. Moreover, ACMG-AMP and Sherloc classifications had a rate of concordance of 64%. ACMG-AMP guidelines presented a higher rate of shift between different variant classes (P=2.3E-13), reflecting the use of more strict evidence criteria in the Sherloc classification framework. Our results show that comprehensive re-analysis of variant classification directly impacts clinical management, highlighting the importance of consistently using new available tools to reinterpret the significance of sequence variants