Located on chromosome 2 with 11 exons, BRCA1-associated ring domain (BARD1) is part of the BRCA1/BARD1 protein complex and associated with breast cancer susceptibility. The protein complex enhances ubiquitin ligase activity, which helps regulate centrosome function, repair DNA, and regulate cell cycles to maintain genetic stability. BARD1 interacts with and stabilizes BRCA1 in the repair of double-strand DNA breaks as part of the homologous recombination pathway.
Biomarker Testing, Risk Counseling, and Screening Recommendations
BARD1 is part of typical multigene testing for germline risk of developing breast cancer. Mulitgene testing approaches increase the possibility of finding a pathogenic variant, including BARD1. Genetic changes include missense pathogenic variants, nonsense pathogenic variants, splice-site pathogenic variants, and deletions.
As a susceptibility biomarker, a BARD1 variant indicates that a patient’s overall estimated risk of developing breast cancer is 20%–40%, most commonly triple-negative breast cancer. Current studies are exploring whether germline pathogenic BARD1 variants are associated with increased risks of developing other malignancies.
BARD1’s moderate penetrance can complicate risk management counseling. The National Comprehensive Cancer Network (NCCN) recommended that patients with a germline pathogenic variant should consider earlier breast cancer screening, with the possible addition of breast magnetic resonance imaging or ultrasound, depending on family history. Personalized patient recommendations should consider models such as the Tyrer-Cuzick model or the Breast Cancer Risk Assessment Tool, also known as the Gail Model, in addition to pathogenic variants, to identify a patient’s absolute risk for developing breast and other cancers.
Screening in individuals with a family history of breast cancer usually begins 10 years before the youngest diagnosis in the family. Although it’s not included in the NCCN recommendations, risk-reducing mastectomies can be considered in the case of multiple breast cancers in the family or early-onset breast cancer.
BARD1 is also a predictive biomarker, in that pathogenic germline or somatic variants in genes such as BARD1 that are associated with repair of DNA double strand breaks through the homologous recombination pathway may indicate a favorable response to PARP inhibitor therapy. Olaparib is a U.S. Food and Drug Administration–approved PARP inhibitor for use in patients with metastatic prostate cancer that has a pathogenic BARD1 variant. Other PARP inhibitors are currently being studied in clinical trials for prostate and other cancers with pathogenic BARD1 variants.
If somatic tumor testing detects a pathogenic variant, patients should be referred to a genetics professional for further assessment and testing to determine whether the variant is germline. Families with a known germline pathogenic variant can be counseled about cascade testing so that individuals can make personalized decisions. Counseling, psychological factors, and interpretation of results are complex with moderate-penetrance genes, such as BARD1, when the best course of action is not always clear.
Some patients may be confused about how test results can help them understand their personal cancer risk. Others may find the unpredictable and unfamiliar nature of the results distressing. Research is needed to help individuals with a germline moderate penetrance pathogenic variant deal with the uncertainty of the results and develop approaches to prepare for and manage risks.
Nurses can provide individuals with information about enrolling in the Prospective Registry of MultiPlex Testing, which calculates penetrance for pathogenic variants in less–well-characterized genes such as BARD1, identifies how variants segregate within families, and provides updates and resources for participants.