Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases

Abstract

Genetic variants of uncertain clinical significance (VUSs) are a common outcome of clinical genetic testing. Locus-specific variant databases (LSDBs) have been established for numerous disease-associated genes as a research tool for the interpretation of genetic sequence variants to facilitate variant interpretation via aggregated data. If LSDBs are to be used for clinical practice, consistent and transparent criteria regarding the deposition and interpretation of variants are vital, as variant classifications are often used to make important and irreversible clinical decisions. In this study, we performed a retrospective analysis of 2017 consecutive BRCA1 and BRCA2 genetic variants identified from 24,650 consecutive patient samples referred to our laboratory to establish an unbiased dataset representative of the types of variants seen in the US patient population, submitted by clinicians and researchers for BRCA1 and BRCA2 testing. We compared the clinical classifications of these variants among five publicly accessible BRCA1 and BRCA2 variant databases: BIC, ClinVar, HGMD (paid version), LOVD, and the UMD databases. Our results show substantial disparity of variant classifications among publicly accessible databases. Furthermore, it appears that discrepant classifications are not the result of a single outlier but widespread disagreement among databases. This study also shows that databases sometimes favor a clinical classification when current best practice guidelines (ACMG/AMP/CAP) would suggest an uncertain classification. Although LSDBs have been well established for research applications, our results suggest several challenges preclude their wider use in clinical practice.

Keywords: BRCA1; BRCA2; Locus-specific variant databases; Variant classification; Variants of uncertain significance.

Fig. 1

Flow diagram of the study design showing BRCA1 and BRCA2 variants identified for study due to detection in the sequencing of 24,650 consecutive patient samples presumed to be unrelated or only distantly related. The number of unique variants among these patients and the number of these variants shared across the BIC, ClinVar, HGMD (paid version), LOVD, and UMD databases are represented

Fig. 2

Agreement between database classifications of variants from an unbiased set of 2017 BRCA1 and BRCA2 unique genetic variants identified in patients. The proportion of agreement is presented according to the number of databases in agreement (x-axis) for (a) all databases examined (BIC, ClinVar, HGMD, LOVD, and UMD) and (b) all databases except HGMD, which had the highest degree of discrepancy. Variants listed in all databases as pathogenic and likely pathogenic were grouped into the “pathogenic” subset (red). Variants listed in all databases as benign or likely benign were grouped into the “benign” subset (blue). “VUS” (grey) represents variants for which all databases described assigned a classification of variants of uncertain significance

Fig. 3

Analysis of the LSDB clinical classifications (benign or pathogenic) of variants considered “VUS” by the criteria outlined in the “Methods” section. Sixty-three of the 124 unique variants shared across the BIC, ClinVar, HGMD (paid version), LOVD, and UMD databases met these criteria. To determine how LSDBs vary in their treatment of these “challenging to classify” variants, we compared the clinical classifications of each “VUS” in all five databases. Variants with conflicting entries of VUS and either pathogenic or benign in the same database are categorized as either pathogenic or benign in the figure (see Table 1). Variants with conflicting classifications of both pathogenic and benign in the same database were excluded from this figure