BRCA2 is a gene that provides the genetic code for a protein that helps the body repair damaged or abnormal DNA. Mutations in the BRCA2 gene can prevent DNA repair and thus predispose carriers to malignancies, including ovarian and breast cancer.
Loss-of-function (LOF) variants of BRCA2 prevent the normal gene DNA repair protein from being produced. Genetic testing can identify individuals with a mutation in the BRCA2 gene, and hereditary cancer surveillance programs have aimed to identify such individuals and provide enhanced screening due to the high likelihood of developing the disease.
Variants of uncertain significance (VUS) in BRCA2 also exist, but scientists do not understand the full impact these mutations have on breast cancer development. Further, clinical testing for BRCA2 does not fully differentiate between LOF and VUS, presenting a major clinical challenge and a need for optimized characterization of all BRCA2 variants.
To address the clinical need to classify different BRCA2 variants, a team of researchers performed a comprehensive study evaluating all the known variants encoding for BRCA2. Their recent publication in Nature provides valuable updates on how BRCA2 informs the clinical management of hereditary cancers. The study used CRISPR-Cas9 technology, a genetic technique that allows researchers to make changes to DNA by adding a specific sequence into a gene.
The researchers evaluated nearly 7,000 variants and assigned them to 7 categories of increasing pathogenicity, a readout of how likely the mutation is to cause cancer.
Variants encoding LOF correlated to increased risk of breast and ovarian cancer. When examining the functional capacity of these variants, the researchers could classify 91% as either pathogenic (increasing cancer risk) or benign (not increasing cancer risk).
The findings of this study provide a valuable resource to oncologists treating patients with hereditary breast and ovarian cancers. By classifying the actual clinical impact of an individual’s BRCA2 mutation, this technology will enable clinicians to determine which BRCA2 carriers have an elevated risk of developing cancer, and which do not. This advancement will provide a valuable tool to facilitate clinical management.
Sources: Cancer Epidemiol. Biomarkers Prev, NEJM, Nature (2024), Nature (2018)
