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.