BRCA Genes: What They Do and Why They Matter
BRCA1 and BRCA2 are among the most well-known genes in human genetics. They encode proteins essential for repairing double-strand DNA breaks through a process called homologous recombination. When either gene carries a pathogenic variant that disables this repair mechanism, cells accumulate DNA damage over time, substantially increasing cancer risk.
Pathogenic variants in BRCA1 and BRCA2 are the strongest known genetic risk factors for breast and ovarian cancer. They also increase the risk of prostate cancer, pancreatic cancer, and in some cases, male breast cancer. Identifying carriers is critical because proven prevention and early detection strategies exist.
What 23andMe Tests: Three Ashkenazi Founder Mutations
The 23andMe Health + Ancestry report includes a BRCA section, but it is important to understand exactly what it covers. 23andMe tests for three specific BRCA variants:
- 185delAG (BRCA1) — Also known as c.68_69delAG. A two-base deletion in exon 2 of BRCA1 that creates a frameshift and premature stop codon.
- 5382insC (BRCA1) — Also known as c.5266dupC. A single-base insertion in exon 20 that causes a frameshift.
- 6174delT (BRCA2) — Also known as c.5946delT. A single-base deletion in exon 11 that causes a frameshift.
These three variants are called founder mutations because they are disproportionately common in individuals of Ashkenazi Jewish descent, where roughly 1 in 40 people carries at least one of them. In the general population, they are much rarer.
What 23andMe Misses
This is the critical point that many people do not fully appreciate: over 1,000 different pathogenic variants have been identified in BRCA1, and over 1,000 in BRCA2. The three variants 23andMe tests represent a tiny fraction of all known pathogenic BRCA mutations. If you are not of Ashkenazi Jewish ancestry, the probability that one of these three specific variants is responsible for a familial BRCA mutation in your family is very low.
A negative result from 23andMe means you do not carry those three specific variants. It does not mean you are free of all BRCA risk. This distinction is clinically important and has been a source of confusion for consumers.
Clinical BRCA Testing vs DTC Testing
Clinical BRCA testing differs from consumer testing in several important ways:
- Coverage — Clinical tests sequence the entire BRCA1 and BRCA2 coding regions and detect large rearrangements (deletions/duplications) that microarrays miss entirely.
- Variant classification — Clinical labs classify variants using ACMG/AMP criteria into five categories: pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign.
- Genetic counseling — Clinical testing includes pre-test and post-test genetic counseling to help you understand results and make informed decisions.
- Insurance coverage — For individuals who meet NCCN testing criteria, clinical BRCA testing is typically covered by insurance under the Affordable Care Act.
- Multi-gene panels — Modern clinical testing often includes additional cancer risk genes beyond BRCA1/BRCA2, such as PALB2, ATM, CHEK2, and others.
When to Get Clinical BRCA Testing
The National Comprehensive Cancer Network (NCCN) recommends clinical genetic testing for individuals who meet any of the following criteria:
- Personal history of breast cancer diagnosed at age 50 or younger
- Personal history of ovarian, fallopian tube, or primary peritoneal cancer at any age
- Personal history of male breast cancer
- Personal history of triple-negative breast cancer at age 60 or younger
- Personal history of two or more primary breast cancers
- Ashkenazi Jewish ancestry with any breast, ovarian, or pancreatic cancer
- A known BRCA pathogenic variant in the family
- First- or second-degree relative meeting any of the above criteria
The Importance of Genetic Counseling
Whether you are considering BRCA testing, have received a positive result, or are trying to interpret a DTC test, genetic counseling is strongly recommended. A certified genetic counselor (CGC) can help you understand your personal and family risk, determine whether clinical testing is appropriate, interpret results including variants of uncertain significance, discuss management options, and address the emotional and psychological aspects of genetic risk information.
You can find a genetic counselor through the National Society of Genetic Counselors (NSGC) directory or ask your primary care physician for a referral.
Explore Your Genetic Data
Use the free SNP Lookup tool to explore SNPs related to cancer risk and other health traits from your 23andMe or AncestryDNA raw data. For a comprehensive genomic profile, upload your data through the Genomics Dashboard.