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.

Assessment of blind predictions of the clinical significance of BRCA1 and BRCA2 variants

“…Although the ENIGMA Consortium had prioritized some variants according to the prior likelihood of pathogenicity, most of the variants were either Benign or Likely Benign. This skew is consistent with the actual proportions of the different clinical significance annotations for BRCA1/2 variants (Cline et al, ). During the course of the CAGI experiment, the ENIGMA Consortium reclassified several of these variants with new evidence.…”

“…This increased rate of BRCA1/2 testing has led to an increasing discovery of new variants, and this rate of variant discovery has outpaced the rate of variant interpretation. Out of 21,695 variants currently listed at BRCA Exchange, the largest public source of BRCA1/2 variation data (Cline et al, 2018), almost half (9,225) have no clinical interpretation in either ClinVar (Landrum & Kattman, 2018) or the Leiden Open Variation Database (LOVD) (Fokkema et al, 2011). Further, only 7,225 so far have expert interpretations by the ENIGMA Consortium (Spurdle et al, 2012), the ClinGen expert panel for curation of variants in BRCA1/2.…”

High-Throughput Functional Evaluation ofBRCA2Variants of Unknown Significance

“…Initially, a total of 107 BRCA2 variants were selected from a curated database, the BRCA Exchange 24 ( Supplementary Table 1 ). Of these, 32, 10, and 65 variants were classified as benign (Class 1/2), pathogenic (Class 4/5), and VUSs (Class 3), respectively, according to the multifactorial five-tier classification system developed by the International Agency for Research on Cancer (IARC) 10,11,18,25,26 .…”

Structural variants at theBRCA1/2loci are a common source of homologous repair deficiency in high grade serous ovarian carcinoma

“…The clinical importance of germline and somatic short variants at BRCA1/2 is well established in cancer, with variants documented in multiple repositories 17,18 . In contrast, the abundance and effects of structural variants (SVs) at BRCA1/2 are not well understood, particularly for large SVs encompassing multi-megabase regions.…”

“…The demonstration of BRCA1/2 loss and detection of HRD is crucial in the management of HGSOC and other cancers to identify patients whose prognosis is markedly improved by the administration of PARP inhibitors [13][14][15] . PARP inhibitors selectively kill cells that are deficient in HR (homology-directed repair) because these cells can neither resolve stalled replication forks nor accurately repair the increased number of double strand breaks that result from the use of these agents 16 .The clinical importance of germline and somatic short variants at BRCA1/2 is well established in cancer, with variants documented in multiple repositories 17,18 . In contrast, the abundance and effects of structural variants (SVs) at BRCA1/2 are not well understood, particularly for large SVs encompassing multi-megabase regions.…”