BRCA2 6174delT (rs80357713): Cancer Risk

BRCA2 (BReast CAncer gene 2) is a critical DNA repair gene. The 6174delT mutation (rs80357713) is the most common of the three Ashkenazi Jewish founder mutations and one of the most frequent pathogenic BRCA2 variants worldwide. While often discussed alongside BRCA1, BRCA2 has distinct risk profiles, including significant prostate cancer risk in men. Understanding this mutation enables proactive cancer prevention.

Understanding BRCA2

BRCA2, like BRCA1, is essential for DNA repair:

• Function: Repairs double-strand DNA breaks via homologous recombination
• Partner: Works with RAD51 protein to repair DNA
• Location: Chromosome 13
• Tumor suppressor: Prevents uncontrolled cell growth

The 6174delT Mutation

This is a frameshift mutation:

• Change: Deletion of thymine at position 6174
• Effect: Shifts reading frame, creates premature stop codon
• Result: Truncated, non-functional BRCA2 protein
• Classification: Pathogenic - causes disease

Understanding Your Status

• Negative: You don't carry this specific mutation (other BRCA mutations possible)
• Positive (heterozygous): You carry one copy - significantly increased cancer risk
• Biallelic: Extremely rare - causes Fanconi anemia (childhood condition)

BRCA2 vs BRCA1: Key Differences

Breast Cancer

• Risk level: Similar to BRCA1 (~45-70% lifetime)
• Age of onset: Slightly later than BRCA1 (often 40s-50s)
• Tumor type: More often hormone receptor-positive (vs. BRCA1 triple-negative)
• Treatment implications: May respond to hormone therapy

Ovarian Cancer

• Lower than BRCA1: ~15-25% lifetime risk (vs. 40-45% for BRCA1)
• Later onset: Often after age 50
• Still significantly elevated: ~10-20x general population risk

Prostate Cancer

• Major BRCA2 concern: ~20-25% lifetime risk for male carriers
• Earlier onset: Often before age 65
• More aggressive: Higher grade, worse prognosis
• BRCA1 risk lower: Makes BRCA2 particularly important for men

Pancreatic Cancer

• Elevated in BRCA2: ~5-10% lifetime risk
• Higher than BRCA1: More significant concern with BRCA2
• Family history: Risk higher if pancreatic cancer in family

Cancer Risk Numbers

Female BRCA2 Carriers

• Breast cancer: 45-70% lifetime risk (vs. 12% general population)
• Ovarian cancer: 15-25% lifetime risk (vs. 1.3% general)
• Contralateral breast: ~30-40% if first breast cancer diagnosed
• Pancreatic cancer: 5-10% lifetime risk

Male BRCA2 Carriers

• Prostate cancer: 20-25% lifetime risk (vs. ~12% general population)
• Male breast cancer: ~8% lifetime risk (vs. 0.1% general)
• Pancreatic cancer: 5-10% lifetime risk

Founder Mutation Background

Ashkenazi Jewish Heritage

• 6174delT is the most common of the three Ashkenazi founder mutations
• ~1.5% of Ashkenazi Jews carry this specific mutation
• Combined with two BRCA1 mutations: ~1 in 40 Ashkenazi Jews is a carrier
• Population bottleneck concentrated these mutations

Other Populations

• Found in Sephardic Jewish communities
• Present in Eastern European populations
• Spread through historical migrations

Screening Recommendations

Breast Cancer Screening (Women)

• Annual breast MRI: Starting at age 25
• Annual mammogram: Starting at age 30
• Clinical breast exam: Every 6-12 months
• Self-awareness: Know your normal, report changes

Ovarian Cancer

• Limited screening value: CA-125 and transvaginal ultrasound not reliable
• Risk-reducing surgery: Recommended, often after age 40 (later than BRCA1)
• Symptom awareness: Report pelvic/abdominal symptoms promptly

Prostate Cancer Screening (Men)

• Start PSA screening: Age 40 (earlier than general population)
• Annual screening: Recommended for BRCA2 carriers
• Digital rectal exam: Part of comprehensive screening
• Consider MRI: If PSA elevated

Pancreatic Cancer Screening

• If family history: Consider EUS or MRI starting age 50
• No family history: Screening value less clear
• Discuss with specialist: Individualized recommendations

Male Breast Cancer

• Annual clinical breast exam recommended
• Breast self-awareness
• Report any lumps or changes promptly

Risk Reduction Options

Surgical Prevention - Women

• Risk-reducing mastectomy: Reduces breast cancer risk by ~90%
• Risk-reducing salpingo-oophorectomy: Consider age 40-45 (later than BRCA1)
• Personal decision: Weigh family planning, quality of life, personal values

Medication Options

• Tamoxifen: May reduce breast cancer risk ~50%
• Oral contraceptives: May reduce ovarian cancer risk
• Discuss: Benefits and risks with oncologist

Lifestyle Factors

• Maintain healthy weight
• Limit alcohol consumption
• Exercise regularly
• Breastfeeding may provide some protection

Treatment Implications

If Cancer Develops

• PARP inhibitors: Highly effective for BRCA2-mutated cancers
• Platinum chemotherapy: Often effective
• Olaparib, talazoparib: FDA-approved for BRCA-mutated breast cancer
• Prostate cancer: PARP inhibitors now approved for BRCA2-mutated prostate cancer

Tumor Testing

• All breast, ovarian, prostate, pancreatic cancers should be tested
• Somatic (tumor-only) BRCA mutations also respond to PARP inhibitors
• Testing guides treatment selection

Family Implications

Inheritance

• Autosomal dominant: 50% chance to pass to each child
• Affects both males and females
• Males can pass mutation and have their own cancer risks

Testing Family

• First-degree relatives should consider testing
• Cascade testing identifies at-risk relatives
• Both male and female relatives should be informed

Prevalence

• Ashkenazi Jews: ~1.5% carry 6174delT specifically
• General population: ~1 in 400-500 carry any BRCA2 mutation
• Most common BRCA2 mutation: In many testing cohorts

Testing Considerations

Consumer Testing Limitations

• Consumer tests often only check founder mutations
• Negative doesn't rule out other BRCA mutations
• Clinical confirmation essential if positive
• Comprehensive testing may be needed

Frequently Asked Questions

I'm a man - why does BRCA2 matter for me?

BRCA2 is particularly important for men because it significantly increases prostate cancer risk (20-25% lifetime) and male breast cancer risk (8%). Prostate cancers in BRCA2 carriers tend to be more aggressive. Early prostate screening starting at age 40, rather than waiting until 50+, is recommended. You can also pass the mutation to daughters, putting them at high risk.

How is BRCA2 different from BRCA1?

While both increase breast and ovarian cancer risk, BRCA2 has some distinctions: ovarian cancer risk is lower (~15-25% vs ~40-45%), prostate cancer risk is higher (making it more important for men), and breast cancers are more often hormone receptor-positive. Risk-reducing ovarian surgery can often be delayed to age 40-45 with BRCA2 vs. 35-40 for BRCA1.

My parent has this mutation - what are my chances?

You have a 50% chance of inheriting the mutation. Genetic testing can tell you definitively. If you didn't inherit it, your risk returns to the general population level and you cannot pass it to your children. If you did inherit it, you'll want to begin enhanced screening and discuss prevention options with your healthcare team.

References

1. Kuchenbaecker KB, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402-2416.
2. Castro E, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757.
3. NCCN Guidelines. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2.2024.