Comparison of BRCA Exchange to BRCA Share.

The BRCA Share [40] repository contains variants from the UMD and the testing labs Quest Diagnostics and Laboratory Corporation of America (LabCorp). The contents of BRCA Share are available to academic researchers free of charge and to commercial partners under a subscription fee. To assess ENIGMA’s concordance with BRCA Share, we analyzed 5,452 variants—most of the BRCA Share set—by running them through the BRCA Exchange pipeline. BRCA Share contained 3,938 variants not assessed by ENIGMA, and BRCA Exchange contained 4,640 variants that were assessed by ENIGMA but not found in BRCA Share. In addition, we considered a consensus classification based on available ClinVar, LOVD, BIC, and ENIGMA classifications. For these consensus classifications, there were 2,228 variants in BRCA Share with no reference assertion in BRCA Exchange and 13,341 with reference assertions in BRCA Exchange but no assessment in BRCA Share. We compared the clinical significance assessments of the BRCA Share variants with the 6,154 assessments from ENIGMA and the 16,565 BRCA Exchange consensus reference interpretations. Overall, the clinical assessments showed a strong similarity. “Most Neutral” or “Likely Neutral” variants in BRCA Share were assessed as “Benign” or “Likely Benign” in BRCA Exchange, and most “Causal” or “Likely Causal” variants in BRCA Share were assessed as “Pathogenic” or “Likely Pathogenic” in BRCA Exchange. The largest differences were in the VUS counts. BRCA Share contained 310 variants designated as VUS that were assessed by ENIGMA—296 as “Benign” or “Likely Benign” and 14 as “Pathogenic.” BRCA Share also contained 473 variants designated VUS that were assessed in BRCA Exchange consensus—431 as “Benign” or “Likely Benign,” and 42 as “Pathogenic” or “Likely Pathogenic” (there are also 1,177 variants listed as VUS in both BRCA Share and BRCA Exchange consensus). In comparison to the number of variant classifications analyzed (5,552 from BRCA Share, 6,154 from ENIGMA, 16,565 from BRCA Exchange), this represents a high rate of concordance, which speaks favorably to the overall quality of the public variation data. Furthermore, the amount of new variant information in BRCA Share, beyond that which is available in BRCA Exchange, illustrates the potential gains of expanding data-sharing efforts. BIC, Breast Cancer Information Core; ENIGMA, Evidence-based Network for the Interpretation of Germline Mutant Alleles; LOVD, Leiden Open Variation Database; UMD, Universal Mutation Database; VUS, variants of uncertain significance.
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