Description

The BRCA Exchange web portal was developed to share known, expert-curated knowledge on the germline variants in BRCA1 and BRCA2, and how these variants may affect an individual’s risk of heritable breast, ovarian, pancreatic and other cancers (HBOC).  This set of variants is obtained by integrating data from genomic variation repositories including ClinVar, LOVD and gnomAD, and annotating these variants according to methods selected and developed in close collaboration with the ENIGMA Consortium, the international expert consortium on research on HBOC variants.   This track hub presents the variants from BRCA Exchange in the context of the human genome, offering further details on each variant in the variant details pages.

The available tracks are:

• BRCA Variants - Shows single nucleotide variants (SNVs) and small insertion/deletion variants of < 50 nucleotides (indels)
• BRCA Structural Variants - Shows variants >=50 nucleotides
• ACMG Popfreq Variants - shows the provisionally-assigned ACMG evidence code for the Population Frequency group, for variants of < 50 nucleotides
• ACMG Popfreq SVs - shows the provisionally-assigned ACMG evidence code for the Population Frequency group, for variants of >= 50 nucleotides

Genomes

We provide data on BRCA variants for the GRCh37 and GRCh38 genomes.

Display Conventions and Configuration

Each variant from BRCA Exchange is represented as one item in this track, with boxes indicating the start and end  genomic coordinates of each variant.  Clicking on a variant will take one to the variant’s track details page, with additional variant data.  Further details on these data are available through the BRCA Exchange Help pages.

• BRCA Variants and BRCA Structural Variants

• Items in red represent variants classified by the ENIGMA VCEP as Pathogenic or Likely Pathogenic.  
• Items in green represent variants classified by the ENIGMA VCEP as Benign or Likely Benign.  
• Items in gray represent variants which have not yet been reviewed by the ENIGMA VCEP.

• VCEP Curation Evidence: Items that convey evidence towards a pathogenic interpretation are colored purple.  Items that convey evidence towards a benign interpretation are colored cyan.  In both cases, the shade of the color indicates the strength of evidence, with darker colors representing stronger evidence.  This includes Population Frequency.

• Dark purple indicates Pathogenic Very Strong evidence, while deep purple indicates Pathogenic Strong, light purple indicates Pathogenic Moderate, and very light purple indicates Pathogenic Supporting.
• Dark cyan indicates Benign Very Strong or Standalone evidence, while deep cyan indicates Benign Strong, light cyan indicates Benign Moderate, and very light cyan indicates Benign Supporting.
• Deep blue indicates an evidence item with no code assigned, either because it failed to meet the evidence thresholds or because of a technical issue.

Methods

The BRCA Exchange variant set is generated monthly, by combining lists of known variants from ClinVar, the gnomAD 2.1 and 3.1 non-cancer subsets, LOVD, The BRCA ExUV resource, and sets of functional assays curated by the ENIGMA Consortium.  Data from these resources are integrated by comparing the GRCh38 genomic coordinates and reference and alternative alleles, merging equivalent variants.  These variants are then annotated by a pipeline that computes in silico prediction scores from methods including from BayesDel, AlignGVGD and SpliceAI.  For more information, see the Help documentation on BRCA Exchange.

Data Availability

All data are freely available for download via https://brcaexchange.org/releases,   

Credits

BRCA Exchange was developed by the BRCA Challenge Consortium, which was launched by the GA4GH to develop responsible approaches for sharing knowledge on genetic variation and disease.  BRCA Exchange was implemented by the labs of Melissa Cline at UC Santa Cruz, Benedict  Paten at UC Santa Cruz and Gunnar Rätsch at ETH Zurich, in close consultation with Amanda Spurdle at QIMR Berghofer.  The Cline and Spurdle labs continue the on-going development of the resource.  For questions, please contact [email protected].

ENIGMA Consortium: https://enigmaconsortium.org/

ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel: https://clinicalgenome.org/affiliation/50087/

References

Cline MS, Liao RG, Parsons MT, Paten B et al. BRCA Challenge: BRCA Exchange as a global resource for variants in BRCA1 and BRCA2, PLoS Genet. 2018 Dec 26;14(12):e1007752. doi: 10.1371/journal.pgen.1007752. PMID: 30586411;  PMCID: PMC6324924

Parsons MT, de la Hoya M, Richardson ME, Tudini E et al. Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ASHG 2024 Aug 13. doi:10.1016/j.ajhg.2024.07.013.