We are delighted to unveil a new feature on BRCA Exchange: the provisional assignments of ACMG evidence codes, computed according to the rules of the ClinGen ENIGMA (BRCA1 and BRCA2) Variant Curation Evidence Panel!
By the procedures of ClinGen and ClinVar, the ACMG/AMP guidelines for sequence variant interpretation define and standardize the forms of evidence that can be used to curate germline variants, and describe how variants can be curated as Benign, Likely Benign, Pathogenic or Likely Pathogenic according to the assembled evidence. These guidelines are very general in nature, with portions that do not apply to all genes. To adapt these generalized rules to specific genes and diseases, the ClinGen Variant Curation Expert Panels (VCEPs) each define a set of rules, based on the ACMG/AMP guidelines, for the curation of variants of the genes within their purview, and generate definitive expert variant curations which are recognized by the U.S. F.D.A. While many variants in ClinVar currently have conflicting classifications, the VCEP rules define the objective standards for the variants within their purview, which addresses many of these conflicts. BRCA1 and BRCA2 variants fall within the purview of the ENIGMA BRCA1 and BRCA2 VCEP. This VCEP consists of an international team of researchers and clinicians drawn largely from the membership of the Evidence-based Network for the Interpretation of Germline Mutation Alleles (ENIGMA) consortium, the expert consortium on the genetics of Heritable Breast and Ovarian Cancer (HBOC) syndrome. After long and careful deliberaton, the ENIGMA VCEP has established its variant curation rules, which have been published in the American Society of Human Genetics.
After the years of research on the BRCA genes, our knowledge, and the VCEP rules, capture many nuances on the impact of BRCA variation. Consequently, these rules can be involved, and difficult for biocurators to apply accurately. To address this pitfall, we are pre-computing the ACMG evidence codes for many categories of evidence, for all variants in BRCA Exchange. Formally, under the ClinGen framework, these evidence code assignments are “provisional”, since for the most part, they have not been reviewed by the VCEP biocuration team. While some variants have been curated by the VCEP, and the biocuration team has reviewed all available evidence, most variants in BRCA Exchange have not yet been curated by the VCEP. However, the set of provisional evidence code assignments has been carefully vetted by the VCEP coordinators together with BRCA Exchange developers, and we anticipate that very few (if any) of these assignments will be changed by the biocurators.
To share these provisional evidence code assignments, we have added a new tile to the BRCA Exchange Variant Details pages, as shown below. For the first release, we are sharing provisional evidence code assignments for the Population Frequency evidence category. In the next release, we will be adding provisional evidence codes for null variation and computational prediction. Ultimately, we aim to share provisional evidence code assignments for most, if not all, of the evidence categories in the VCEP rules.
We hope that by sharing these provisional evidence code assignments, we will enable curators beyond the VCEP to curate BRCA variants according to the VCEP rules, without incurring the costs of evaluating the rules themselves. These data are available via BRCA Exchange and on the BRCA Exchange Track Hub of the UCSC Genome Browser, and are available for download via both platforms. If you have any questions or concerns, please contact us at brcaexchange@gmail.com.
