Consistency of BRCA1 and BRCA2 Variant Classifications Among Clinical Diagnostic Laboratories

Abstract

Purpose Genetic tests of cancer predisposition genes, BRCA1 and BRCA2, inform significant clinical decisions for both physicians and patients. Most uncovered variants are benign, and determining which few are pathogenic—disease causing—is sometimes challenging and can potentially be inconsistent among laboratories. The ClinVar database makes deidentified clinical variant classifications from multiple laboratories publicly available for comparison and review, per recommendations by the American Medical Association, the American College of Medical Genetics, the National Society for Genetic Counselors, and other organizations. Methods Classifications of more than 2,000 BRCA1/2 variants in ClinVar that represent approximately 22,000 patients were dichotomized as clinically actionable or not actionable and compared among as many as seven laboratories. The properties of these variants and classification differences were investigated in detail. Results Per-variant concordance was 98.5% (CI, 97.9% to 99.0%). All discordant variants were rare; thus, per-patient concordance was estimated to be higher (99.7%). ClinVar facilitated resolution of many of the discordant variants, and concordance increased to 99.0% per variant and 99.8% per patient when reclassified, but not yet resubmitted, variants and submission errors were addressed. Most of the remaining discordances seemed to involve either legitimate differences in expert judgment regarding particular scientific evidence or were classifications that predated the availability of important scientific evidence. Conclusion Significant classification disagreements among professional clinical laboratories represented in ClinVar are infrequent yet important. Unrestricted sharing of clinical genetic data allows detailed interlaboratory quality control and peer review, as exemplified by this study.