Quick Uptakes: Taking the Uncertainty Out of Interpreting BRCA Variants
Abstract
The Problem
Testing for BRCA1 and BRCA2 mutations identifies both benign and pathogenic genetic variants. But information about specific variants, particularly those of uncertain clinical significance (VUS), often isn’t systematically curated, expertly reviewed, or easily searchable. In addition, different laboratories sometimes interpret test results differently.
Downstream Risk
Some patients whose variants don’t have a clear clinical meaning might seek or receive unnecessary care.
Statistically Speaking
About 3% of BRCA1 and BRCA2 findings on genetic tests are VUS. An estimated 15% to 20% of them are likely to be disease causing. As more people undergo genetic testing, clinicians will continue to see VUS.
Strategic Move
The Global Alliance for Genomics and Health in 2014 decided that “big data” could shine a spotlight on VUS in BRCA1 and BRCA2 genes. Plans emerged to launch an international effort aimed at creating a 1-stop shop to share information about BRCA1 and BRCA2 variants.
The Solution
Instead of wading through many databases with information that sometimes hasn’t been properly vetted, the BRCA Exchange was created as a central repository for expertly reviewed genetic variation data. It’s a web portal containing information from clinicians, clinical laboratories, and researchers around the world as well as existing clinical databases, including:
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ClinVar, a publicly available archive of genetic variants and their association with human phenotypes.
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Breast Cancer Information Core, an open access breast cancer mutation database.
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Leiden Open Variation Database—an open source database of gene variants.
Currently, the BRCA Exchange includes more than 20 000 unique BRCA1 and BRCA2 variants. The international Evidence-based Network for the Interpretation of Germline Mutant Alleles consortium provides expert classification of more than 6100 of those variants. So far, 3700 are classified as pathogenic.
RPR Commentary
For those who are trying to answer patients’ questions about BRCA variants, there’s a free app for that (BRCA Exchange). James W. Mold, MD, MPH