Abstract
BackgroundBRCA1/2testing is crucial to guide clinical decisions in patients with hereditary breast/ovarian cancer, but detection of variants of uncertain significance (VUSs) prevents proper management of carriers. The ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles)BRCA1/2Variant Curation Expert Panel (VCEP) has recently developedBRCA1/2variant classification guidelines consistent with ClinGen processes, specified against the ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular-Pathology) classification framework.MethodsThe ClinGen-approvedBRCA1/2-specified ACMG/AMP classification guidelines were applied toBRCA1/2VUSs identified from 2011 to 2022 in a series of patients, retrieving information from the VCEP documentation, public databases, literature and ENIGMA unpublished data. Then, we critically re-evaluated carrier families based on new results and checked consistency of updated classification with main sources for clinical interpretation ofBRCA1/2variants.ResultsAmong 166 VUSs detected in 231 index cases, 135 (81.3%) found in 197 index cases were classified by applyingBRCA1/2-specified ACMG/AMP criteria: 128 (94.8%) as Benign/Likely Benign and 7 (5.2%) as Pathogenic/Likely Pathogenic. The average time from the first report as ‘VUS’ to classification using this approach was 49.4 months. Considering that 15 of these variants found in 64 families had already been internally reclassified prior to this work, this study provided 121 new reclassifications among the 151 (80.1%) remaining VUSs, relevant to 133/167 (79.6%) families.ConclusionsThese results demonstrated the effectiveness of newBRCA1/2ACMG/AMP classification guidelines for VUS classification within a clinical cohort, and their important clinical impact. Furthermore, they suggested a cadence of no more than 3 years for regular review of VUSs, which however requires time, expertise and resources.
Subject
Genetics (clinical),Genetics