BRCA1 and BRCA2 are among the most studied genes in all of medicine. Their names appear constantly in discussions of hereditary cancer risk. But what do these genes actually do — and what does it mean to carry a pathogenic variant in one of them?

What BRCA1 and BRCA2 Do

Both BRCA1 and BRCA2 encode proteins that play critical roles in repairing a specific type of DNA damage called double-strand breaks — places where both strands of the DNA double helix are cut.

Double-strand breaks are particularly dangerous because they can lead to large-scale chromosomal rearrangements if not repaired accurately. The BRCA1 and BRCA2 proteins help coordinate a repair process called homologous recombination, which uses the intact copy of the chromosome as a template to repair the break accurately.

When BRCA1 or BRCA2 function is lost, cells must rely on less accurate repair pathways. Errors accumulate, and over time, some cells may acquire the additional changes needed to become cancerous.

What a Pathogenic Variant Means

A pathogenic variant in BRCA1 or BRCA2 means that one copy of the gene carries a change that disrupts normal protein function.

Because you have two copies of most genes, one functional copy often provides enough repair capacity for normal cell function. However, if the second copy is inactivated by a somatic mutation in a particular cell — the "second hit" in Knudson's two-hit model — that cell loses BRCA-mediated repair entirely.

This is why carrying a germline pathogenic variant raises cancer risk without guaranteeing cancer: the second hit must still occur in a specific cell.

Cancer Risks Associated With BRCA1 and BRCA2

Pathogenic variants in BRCA1 and BRCA2 are associated with elevated lifetime risks of several cancers:

Breast cancer (female):

• BRCA1: approximately 50–72% lifetime risk
• BRCA2: approximately 45–69% lifetime risk (compared to approximately 12% average population risk)

Ovarian cancer:

• BRCA1: approximately 44–46% lifetime risk
• BRCA2: approximately 10–27% lifetime risk (compared to approximately 1–2% average population risk)

Pancreatic cancer: modestly elevated risk, particularly with BRCA2

Prostate cancer: elevated risk, particularly with BRCA2

Male breast cancer: elevated risk with both genes, particularly BRCA2

These figures are estimates from large studies and vary depending on family history, the specific variant, and other factors.

Who Should Consider BRCA Testing?

Current guidelines recommend considering BRCA1/2 testing for individuals with:

• A personal or family history of breast cancer diagnosed at a young age (typically under 50)
• Ovarian cancer at any age
• Male breast cancer
• Triple-negative breast cancer
• Pancreatic cancer with a family history of BRCA-related cancers
• Ashkenazi Jewish ancestry (founder variants are more common in this population)
• A known BRCA1 or BRCA2 pathogenic variant in a family member

What Can Be Done With a Positive Result?

A pathogenic BRCA1 or BRCA2 result is not a diagnosis — it is information that enables action. Evidence-based options include:

• Enhanced surveillance: more frequent mammography, breast MRI, or other imaging
• Risk-reducing surgery: prophylactic mastectomy or salpingo-oophorectomy
• Chemoprevention: medications that may reduce breast cancer risk
• Cascade testing: testing of relatives to identify others who may benefit
• Targeted therapy: PARP inhibitors are approved for certain BRCA-related cancers

At Genetic Insights, we help patients understand what a BRCA result means for their specific situation and connect them with appropriate management options.

Key Takeaway: BRCA1 and BRCA2 are DNA repair genes. Pathogenic variants raise the risk of breast, ovarian, pancreatic, and other cancers by impairing accurate repair of double-strand DNA breaks. A positive result enables evidence-based surveillance and prevention.

Sources: NCCN Guidelines — Hereditary Breast and Ovarian Cancer; NCI BRCA Fact Sheet