Consistency of and Variant Classifications Among Clinical Diagnostic Laboratories.

Background: Genetic tests of the cancer predisposition genes and 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 de-identified clinical variant classifications from multiple laboratories publicly available for comparison and review, per recommendations of the American Medical Association (AMA), the American College of Medical Genetics (ACMG), the National Society for Genetic Counselors (NSGC), and other organizations.

Methods: Classifications of more than 2000 variants in ClinVar representing approximately 22,000 patients were dichotomized as clinically actionable or not actionable and compared across up to seven laboratories. The properties of these variants and classification differences were investigated in detail.

Results: Per-variant concordance was 98.5% (CI 97.9%-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 appeared to involve either legitimate differences in expert judgment regarding particular scientific evidence, or were classifications that predated availability of important scientific evidence.

Conclusions: Significant classification disagreements among the professional clinical laboratories represented in ClinVar are infrequent yet important. The unrestricted sharing of clinical genetic data allows detailed interlaboratory quality control and peer review, as exemplified by this study.