Dataset Information

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.

SUBMITTER: Cline MS

PROVIDER: S-EPMC6324924 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Cline Melissa S MS Liao Rachel G RG Parsons Michael T MT Paten Benedict B Alquaddoomi Faisal F Antoniou Antonis A Baxter Samantha S Brody Larry L Cook-Deegan Robert R Coffin Amy A Couch Fergus J FJ Craft Brian B Currie Robert R Dlott Chloe C CC Dolman Lena L den Dunnen Johan T JT Dyke Stephanie O M SOM Domchek Susan M SM Easton Douglas D Fischmann Zachary Z Foulkes William D WD Garber Judy J Goldgar David D Goldman Mary J MJ Goodhand Peter P Harrison Steven S Haussler David D Kato Kazuto K Knoppers Bartha B Markello Charles C Nussbaum Robert R Offit Kenneth K Plon Sharon E SE Rashbass Jem J Rehm Heidi L HL Robson Mark M Rubinstein Wendy S WS Stoppa-Lyonnet Dominique D Tavtigian Sean S Thorogood Adrian A Zhang Can C Zimmermann Marc M Burn John J Chanock Stephen S Rätsch Gunnar G Spurdle Amanda B AB

PLoS genetics 20181226 12

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, ne ...[more]

PMID: 30586411

Similar Datasets

Project description:ImportanceThe clinical importance of genetic testing of BRCA1 and BRCA2 in breast, ovarian, prostate, and pancreatic cancers is widely recognized. However, there is insufficient evidence to include other cancer types that are potentially associated with BRCA1 and BRCA2 in clinical management guidelines.ObjectiveTo evaluate the association of BRCA1 and BRCA2 pathogenic variants with additional cancer types and their clinical characteristics in 100 914 individuals across 14 cancer types.Design, setting, and participantsThis case-control analysis to identify cancer types and clinical characteristics associated with pathogenic variants in BRCA1 and BRCA2 included DNA samples and clinical information from 63 828 patients with 14 common cancer types and 37 086 controls that were sourced from a multi-institutional hospital-based registry, BioBank Japan, between April 2003 and March 2018. The data were analyzed between August 2019 and October 2021.Main outcomes and measuresGermline pathogenic variants in coding regions and 2 bp flanking intronic sequences in BRCA1 and BRCA2 were identified by a multiplex polymerase chain reaction-based target sequence method. Associations of (likely) pathogenic variants with each cancer type were assessed by comparing pathogenic variant carrier frequency between patients in each cancer type and controls.ResultsA total of 65 108 patients (mean [SD] age at diagnosis, 64.1 [11.6] years; 27 531 [42.3%] female) and 38 153 controls (mean [SD] age at registration, 61.8 [14.6] years; 17 911 [46.9%] female) were included in this study. A total of 315 unique pathogenic variants were identified. Pathogenic variants were associated with P < 1 × 10-4 with an odds ratio (OR) of greater than 4.0 in biliary tract cancer (OR, 17.4; 95% CI, 5.8-51.9) in BRCA1, esophageal cancer (OR, 5.6; 95% CI, 2.9-11.0) in BRCA2, and gastric cancer (OR, 5.2; 95% CI, 2.6-10.5) in BRCA1, and (OR, 4.7; 95% CI, 3.1-7.1) in BRCA2 in addition to the 4 established cancer types. We also observed an association with 2 and 4 other cancer types in BRCA1 and BRCA2, respectively. Biliary tract, female breast, ovarian, and prostate cancers showed enrichment of carrier patients according to the increased number of reported cancer types in relatives.Conclusions and relevanceThe results of this large-scale registry-based case-control study suggest that pathogenic variants in BRCA1 and BRCA2 were associated with the risk of 7 cancer types. These results indicate broader clinical relevance of BRCA1 and BRCA2 genetic testing.

Project description:BACKGROUND: BRCA1 and BRCA2 germline mutations predispose heterozygous carriers to hereditary breast/ovarian cancer. However, unclassified variants (UVs) (variants with unknown clinical significance) and missense polymorphisms in BRCA1 and BRCA2 genes pose a problem in genetic counseling, as their impact on risk of breast and ovarian cancer is still unclear. The objective of our study was to identify UVs and missense polymorphisms in Algerian breast/ovarian cancer patients and relatives tested previously for BRCA1 and BRCA2 genes germline mutations analysis. METHODS: We analyzed 101 DNA samples from 79 breast/ovarian cancer families. The approach used is based on BRCA1 and BRCA2 sequence variants screening by SSCP or High-Resolution Melting (HRM) curve analysis followed by direct sequencing. In silico analyses have been performed using different bioinformatics programs to individualize genetics variations that can disrupt the BRCA1 and BRCA2 genes function. RESULTS: Among 80 UVs and polymorphisms detected in BRCA1/2 genes (33 BRCA1 and 47 BRCA2), 31 were new UVs (10 BRCA1 and 21 BRCA2), 7 were rare UVs (4 BRCA1 and 3 BRCA2) and 42 were polymorphic variants (19 BRCA1 and 23 BRCA2). Moreover, 8 new missense UVs identified in this study: two BRCA1 (c.4066C>A/p.Gln1356Lys, c.4901G>T/p.Arg1634Met) located respectively in exons 11 and 16, and six BRCA2 (c.1099G>A/p.Asp367Asn, c.2636C>A/p.Ser879Tyr, c.3868T>A/p.Cys1290Ser, c.5428G>T/p.Val1810Phe, c.6346C>G/p.His2116Asp and c.9256G>A/p.Gly3086Arg) located respectively in exons 10, 11 and 24, show a damaging PSIC score yielded by PolyPhen2 program and could be pathogenic. In addition, 5 new BRCA} missense UVs out of six that were found to be damaging by PolyPhen2 program, also were deleterious according to SIFT program. The rare BRCA1 UV c.5332G>A/p.Asp1778Asn was found here for the first time in co-occurrence in trans with the deleterious BRCA1 mutation c.798_799delTT/p.Ser267LysfsX19 in young breast cancer patient. Moreover, 10 new identified intronic variants with unknown clinical significance (3 BRCA1 and 7 BRCA2) in the present study, could be considered as benign, because GeneSplicer, SpliceSiteFinder and MaxEntScan prediction programs show no splice site alteration for these variants. Several missense polymorphisms of BRCA1 c.2612C>T/p.Pro871Leu, c.3548A>G/p.Lys1183Arg, c.4837A>G/p.Ser1613Gly and BRCA2 c.865A>C/p.Asn289His, c.1114A>C/p.Asn372His, c.2971A>G/p.Asn991Asp, c.7150C>A/p.Gly2384Lys have been identified with high frequency in patients who were tested negative for BRCA1 and BRCA2 mutations. These missense polymorphisms could have a role as susceptibility breast cancer markers in Algerian breast/ovarian cancer families where pathological BRCA1 and BRCA2 mutations were not present. CONCLUSIONS: For the first time, UVs and missense polymorphisms in BRCA1 and BRCA2 genes have been identified in Algerian breast/ovarian cancer families. Evaluation of breast/ovarian cancer risk induced by the eight new missense UVs and common polymorphisms detected in our present work is on going in a larger study.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets