Variant classifications in BRCA1 and BRCA2: A systematic analysis of interlaboratory concordance

1592Background: Most laboratories use publicly available literature, databases, and expertise to determine the pathogenicity of genetic variants. Recently, discordances between public databases have been raised as a concern, most prominently by those who use proprietary data in their classification processes. However, the clinical impact of these differences is unclear, as experienced and responsible lab directors never simply copy variant classifications from any public database. Instead, they critically evaluate underlying evidence and determine classifications following established guidelines (i.e., ACMG 2015). In prior work, we observed 99.8% concordance between two labs in 975 prospectively accrued patients (Lincoln et al., JMD 2015). Here we evaluated classification concordance among multiple labs in a much larger patient population. Methods: We analyzed the BRCA Exchange dataset, based on ClinVar and under development by the Global Alliance for Genomics and Health's BRCA Challenge collaboration. We...