Abstract
PurposeGenetic 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.MethodsClassifications 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.ResultsPer-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.ConclusionSignificant 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.
Highlights
Hereditary breast and ovarian cancer is a cancer predisposition syndrome that results from inherited— that is, germline—loss-of-function mutations in BRCA1 or BRCA2 genes,collectively,BRCA1/2.Such pathogenic, or disease-causing, genetic variants result in a 40% to 80% lifetime risk of developing breast cancer, an 11% to 40% risk of ovarian cancer, and striking increases in the risk of male breast, pancreatic, and prostate cancers.[1,2]
One in 250 individuals of European descent are born with a pathogenic variant in BRCA1/2, and prevalence is much higher in certain populations—for example, Ashkenazi Jews.[5,6]
Recognizing that shared knowledge about genetic variants is critical to high-quality medical care, the National Institutes of Health established ClinVar, a public database of clinically observed genetic variants, their pathogenicity classifications from various laboratories, and a summary of the scientific evidence used in those classifications.[21,22,23,24,25]
Summary
Hereditary breast and ovarian cancer is a cancer predisposition syndrome that results from inherited— that is, germline—loss-of-function mutations in BRCA1 or BRCA2 genes,collectively,BRCA1/2.Such pathogenic, or disease-causing, genetic variants result in a 40% to 80% lifetime risk of developing breast cancer, an 11% to 40% risk of ovarian cancer, and striking increases in the risk of male breast, pancreatic, and prostate cancers.[1,2] Up to 10% of breast cancers are caused by these genes.[3,4] Approximately one in 250 individuals of European descent are born with a pathogenic variant in BRCA1/2, and prevalence is much higher in certain populations—for example, Ashkenazi Jews.[5,6]Decades of clinical testing and research have uncovered tens of thousands of BRCA1/2 genetic variants across the human population.[7]. The company used its monopoly to accumulate a substantial database of variants that it ceased releasing publicly in 2006 and from which it claims a competitive advantage.[15,16,17] This practice is contrary to the recommendations of the American Medical Association (AMA), the ACMG, the National Society for Genetic Counselors, and other organizations.[18,19,20] Recognizing that shared knowledge about genetic variants is critical to high-quality medical care, the National Institutes of Health established ClinVar, a public database of clinically observed genetic variants, their pathogenicity classifications from various laboratories, and a summary of the scientific evidence used in those classifications.[21,22,23,24,25] Whereas many commercial and academic laboratories collaboratively submit data to ClinVar, others, including Myriad, do not. A substantial Myriad Genetics data set has been submitted by ordering clinicians and patients through the Sharing Clinical Reports Project (SCRP).[13,26] In this study, we used publicly available data from ClinVar to assess agreement among clinical laboratories for classifications of BRCA1/2 variants
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