Genetic Disorder Reference Sheet: BRCA1 and BRCA2 Hereditary Cancers
BRCA1- or BRCA2-associated hereditary breast and ovarian cancer is the most common form (https://www.ncbi.nlm.nih.gov/books/NBK1247) of hereditary breast and ovarian cancer. The prevalence of BRCA1 and BRCA2 pathogenic variants in the general population is estimated at 1 in 400–500 people, although it increases to 1 in 40 for those of Ashkenazi Jewish ancestry, which is linked to three founder pathogenic variants (BRCA1 c.68_69delAG, BRCA1c.5266dupC, and BRCA2 c.5946delT).
Understanding whether an individual carries a pathogenic BRCA1 or BRCA2 variant has implications for cancer prevention, early detection, and treatment strategies in BRCA1- or BRCA2-related malignancies. Key indicators (https://doi.org/10.1136/gutjnl-2019-319352) for referral to genetics professionals for evaluation (https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf) of BRCA1- or BRCA2-associated cancer risk and possible testing (https://www.ncbi.nlm.nih.gov/books/NBK1247) include:
- Breast cancer diagnosed at age 45 or younger
- Ovarian cancer
- Multiple primary breast cancers in one or both breasts
- Male breast cancer
- Pancreatic cancer
- Triple-negative (ER-negative, PR-negative, and HER2/neu-negative) breast cancer, diagnosed before age 60
- Combination of pancreatic cancer or prostate cancer (Gleason score ≥ 7) with breast cancer or ovarian cancer
- Breast cancer diagnosed at any age with Ashkenazi Jewish ancestry
- Two or more relatives with breast cancer, one younger than age 50
- Three or more relatives with breast cancer at any age
- BRCA1 or BRCA2 pathogenic variant previously identified in the family
Both men and women are at increased risk for developing multiple cancers if they have a pathogenic BRCA1 or BRCA2 variant. Not every individual with a pathogenic variant develops cancer because of incomplete penetrance, cancer risk reduction from prophylactic surgery, or early death, and risk differs slightly between BRCA1 or BRCA2 pathogenic variants. See the table for specific risk increases for each cancer and variant.
People who have a pathogenic BRCA1 or BRCA2 variant should follow recommended guidelines for increased cancer prevention and early detection strategies.
Identifying a pathogenic BRCA1 or BRCA2 variant may also influence the choice of targeted therapy or the appropriateness of adding a PARP inhibitor to therapy. For example, olaparib has been approved in various settings (https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208558s001lbl.pdf) for breast, ovarian, prostate, and pancreatic cancer in people with pathogenic BRCA1 or BRCA2 variants.
Women of childbearing age should be informed that Fanconi anemia is associated with having two copies of a BRCA2 pathogenic variant (one from each parent). The chance of having a child with Fanconi anemia is 25% for every pregnancy (https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf) if both parents have a pathogenic variant.
Individuals and families with a known BRCA1 or BRCA2 pathogenic variant are often overwhelmed by the risk information and complex recommendations for cancer prevention and early detection. Oncology nurses can direct patients to the many organizations that offer support, including:
- Bright Pink (http://brightpink.org/) has resources for women to know their risk and manage their health proactively.
- Familial Ovarian Cancer Registry (http://ovariancancer.com/) connects patients to resources that advance research for ovarian cancer.
- FORCE: Facing Our Risk of Cancer Empowered (http://facingourrisk.org/) provides support and educational resources for individuals with hereditary breast and ovarian cancer syndromes.
- Sharsheret (http://sharsheret.org/) has information for Jewish women and families with breast and ovarian cancer.
Resources and interprofessional, coordinated care for the entire family offer the best hope for successful prevention, early detection, and management of BRCA1- or BRCA2-related malignancies.
Editor’s note: For definitions of many of the genetics and genomics terms used in this article, visit ons.org/genomics-taxonomy (http://ons.org/genomics-taxonomy).