Dataset Information

Consistency of BRCA1 and BRCA2 Variant Classifications Among Clinical Diagnostic Laboratories.

ABSTRACT: Genetic tests of the 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 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.Classifications of more than 2000 BRCA1/2 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.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.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.

SUBMITTER: Lincoln SE

PROVIDER: S-EPMC5542009 | biostudies-other | 2017 Jul

REPOSITORIES: biostudies-other

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Publications

Consistency of <i>BRCA1</i> and <i>BRCA2</i> Variant Classifications Among Clinical Diagnostic Laboratories.

Lincoln Stephen E SE Yang Shan S Cline Melissa S MS Kobayashi Yuya Y Zhang Can C Topper Scott S Haussler David D Paten Benedict B Nussbaum Robert L RL

JCO precision oncology 20170411

<h4>Background</h4>Genetic tests of the cancer predisposition genes <i>BRCA1</i> and <i>BRCA2</i> 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 rec ...[more]

PMID: 28782058

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Project description:Pathogenic germline mutations in BRCA1 or BRCA2 are detected in less than one third of families with a strong history of breast cancer. It is therefore expected that mutations still remain undetected by currently used screening methods. In addition, a growing number of BRCA1/2 sequence variants of unclear pathogen significance are found in the families, constituting an increasing clinical challenge. New methods are therefore needed to improve the detection rate and aid the interpretation of the clinically uncertain variants. In this study we analyzed a series of 33 BRCA1, 22 BRCA2, and 128 sporadic tumors by RNA profiling to investigate the classification potential of RNA profiles to predict BRCA1/2 mutation status. We found that breast tumors from BRCA1 and BRCA2 mutation carriers display characteristic RNA expression patterns, allowing them to be distinguished from sporadic tumors. The majority of BRCA1 tumors were basal-like while BRCA2 tumors were mainly luminal B. Using RNA profiles, we were able to distinguish BRCA1 tumors from sporadic tumors among basal-like tumors with 83% accuracy and BRCA2 from sporadic tumors among luminal B tumors with 89% accuracy. Furthermore, subtype-specific BRCA1/2 gene signatures were successfully validated in two independent data sets with high accuracies. Although additional validation studies are required, indication of BRCA1/2 involvement (“BRCAness”) by RNA profiling could potentially be valuable as a tool for distinguishing pathogenic mutations from benign variants, for identification of undetected mutation carriers, and for selecting patients sensitive to new therapeutics such as PARP inhibitors. Gene expression profiling of 183 breast tumor samples. Breast tumors from hereditary breast cancer patients carrying a pathogenic BRCA1 (n=33) or BRCA2 (n=22) germ-line mutation were included in the study. Serving as a representative control group, primary breast tumor samples (n=128) were randomly selected. The study was conducted using Agilent-029949 Custom SurePrint G3 Human GE 8x60K Microarray platform. For cross-platform validation, a subset of the tumor samples (92 of the 183 samples) were analyzed by our in-house spotted microarray platform.

Dataset Information

Consistency of BRCA1 and BRCA2 Variant Classifications Among Clinical Diagnostic Laboratories.

Publications

Consistency of <i>BRCA1</i> and <i>BRCA2</i> Variant Classifications Among Clinical Diagnostic Laboratories.

Similar Datasets

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