BRCA Challenge: BRCA Exchange as a global resource for variants in BRCA1 and BRCA2

Abstract

The BRCA Challenge is a long-term data-sharing project initiated within the Global Alliance for Genomics and Health (GA4GH) to aggregate BRCA1 and BRCA2 data to support highly collaborative research activities. Its goal is to generate an informed and current understanding of the impact of genetic variation on cancer risk across the iconic cancer predisposition genes, BRCA1 and BRCA2. Initially, reported variants in BRCA1 and BRCA2 available from public databases were integrated into a single, newly created site, www.brcaexchange.org. The purpose of the BRCA Exchange is to provide the community with a reliable and easily accessible record of variants interpreted for a high-penetrance phenotype. More than 20,000 variants have been aggregated, three times the number found in the next-largest public database at the project's outset, of which approximately 7,250 have expert classifications. The data set is based on shared information from existing clinical databases-Breast Cancer Information Core (BIC), ClinVar, and the Leiden Open Variation Database (LOVD)-as well as population databases, all linked to a single point of access. The BRCA Challenge has brought together the existing international Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium expert panel, along with expert clinicians, diagnosticians, researchers, and database providers, all with a common goal of advancing our understanding of BRCA1 and BRCA2 variation. Ongoing work includes direct contact with national centers with access to BRCA1 and BRCA2 diagnostic data to encourage data sharing, development of methods suitable for extraction of genetic variation at the level of individual laboratory reports, and engagement with participant communities to enable a more comprehensive understanding of the clinical significance of genetic variation in BRCA1 and BRCA2.

Fig 1. Data flow in the BRCA Exchange pipeline.

BRCA Exchange combines information from major public sources to offer a comprehensive view of BRCA variants from a single web portal. It combines variant information from ClinVar, ENIGMA (as the ClinGen expert panel on BRCA variation) and LOVD (blue); population frequency data from 1000 Genomes, ExAC, and the ESP (red); and BRCA-specific information from the BIC on BRCA 1 and 2 Ex-UV (green). Each month, BRCA Exchange collects variant data from these sources and translates them into a consistent representation. It verifies that all variants are consistent in the reference bases with the reference human genome and discards any variant data that are inconsistent with the genome. Next, it identifies functionally equivalent variants, in which two or more variants might produce the same alternative allele despite distinct representation, and merges equivalencies to generate a set of distinct BRCA variants. It gathers annotations, such as functional impact terms and alternative variant names. Finally, it compares the new variant data to the previous month to identify any variants that are new or updated. These data are shared publicly at brcaexchange.org. The ENIGMA consortium analyzes these aggregated data to determine the clinical significance of unreviewed variants and deposits these interpretations in ClinVar, completing the cycle of information. BIC, Breast Cancer Information Core; ENIGMA, Evidence-based Network for the Interpretation of Germline Mutant Alleles; ESP, Exome Sequencing Project; ExAC, Exome Aggregation Consortium; BRCA Ex-UV, BRCA1 and BRCA2 Ex-UV; GRCh38, Genome Reference Consortium Human Build 38 Organism; LOVD, Leiden Open Variation Database; TCGA, The Cancer Genome Atlas; TSV, Tab Separated Values; VCF, Variant Format Call; XML, Extensible Markup Language.

Fig 2. Venn diagram showing variants per large contributing data repositories, with variant overlap between repositories indicated.

Allele frequency databases currently include ExAC, 1000 Genomes, and ESP. ESP, Exome Sequencing Project; ExAC, Exome Aggregation Consortium; LOVD, Leiden Open Variation Database.

Fig 3. ENIGMA variant classification process.

ENIGMA, Evidence-based Network for the Interpretation of Germline Mutant Alleles; ExAC, Exome Aggregation Consortium; gnomAD, Genome Aggregation Database; HGVS, Human Genome Variation Society; ins-del, insertion-deletions; UTR, untranslated region; 1000G, 1,000 Genomes Project.