BRCA1 5382insC (rs80357906): Cancer Risk

BRCA1 (BReast CAncer gene 1) is a tumor suppressor gene critical for DNA repair. The 5382insC mutation (rs80357906) is one of three Ashkenazi Jewish founder mutations and is among the most common pathogenic BRCA1 variants worldwide. Carriers have significantly increased lifetime risk of breast and ovarian cancer, but knowledge of carrier status enables proactive screening and risk reduction strategies.

Understanding BRCA1

BRCA1 is a crucial DNA repair gene:

• Function: Repairs double-strand DNA breaks through homologous recombination
• Tumor suppressor: Prevents uncontrolled cell growth
• Location: Chromosome 17
• Normal function: Protects against cancer development

The 5382insC Mutation

This is a frameshift mutation:

• Change: Insertion of cytosine at position 5382
• Effect: Shifts reading frame, creates premature stop codon
• Result: Truncated, non-functional BRCA1 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
• Note: BRCA mutations are dominant - one copy is enough to increase risk

Cancer Risk Implications

Breast Cancer Risk

• General population: ~12% lifetime risk
• BRCA1 carriers: ~55-70% lifetime risk
• Earlier onset: Often diagnosed before age 50
• Second primary: Higher risk of contralateral breast cancer
• Tumor type: Often triple-negative breast cancer

Ovarian Cancer Risk

• General population: ~1.3% lifetime risk
• BRCA1 carriers: ~40-45% lifetime risk
• Often diagnosed: Ages 40-60
• No effective screening: Makes prevention important

Other Cancer Risks

• Fallopian tube cancer: Increased risk
• Peritoneal cancer: Increased risk
• Pancreatic cancer: Modestly increased
• Male breast cancer: Increased (though absolute risk still low)

Founder Mutation Background

Ashkenazi Jewish Heritage

• 5382insC is one of three Ashkenazi founder mutations
• The others: BRCA1 185delAG and BRCA2 6174delT
• ~1 in 40 Ashkenazi Jews carries one of these three
• Genetic bottleneck effect concentrated these mutations

Also Found In

• Eastern European populations
• Polish population (relatively common)
• Russian population
• Other populations due to historical migration

Screening Recommendations

Breast Cancer Screening

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

Ovarian Cancer

• No reliable screening: CA-125 and transvaginal ultrasound have limitations
• Risk-reducing surgery: Often recommended after childbearing complete
• Clinical evaluation: Report any pelvic/abdominal symptoms promptly

Other Screening

• Discuss pancreatic cancer screening if family history
• Prostate cancer screening for male carriers
• Individualized based on personal/family history

Risk Reduction Options

Surgical Prevention

• Risk-reducing mastectomy: Reduces breast cancer risk by ~90%
• Risk-reducing salpingo-oophorectomy: Removes ovaries and fallopian tubes
• Timing: Usually recommended ages 35-40 for ovarian prevention
• Personal decision: Consider family planning, personal values

Medication Options

• Tamoxifen: May reduce breast cancer risk ~50%
• Oral contraceptives: May reduce ovarian cancer risk
• Discuss benefits/risks: With your oncologist

Lifestyle Factors

• Maintain healthy weight
• Limit alcohol consumption
• Exercise regularly
• Breastfeeding may provide some protection
• Note: Lifestyle can modify but not eliminate elevated risk

Treatment Implications

If Cancer Develops

• PARP inhibitors: Particularly effective for BRCA-mutated cancers
• Platinum chemotherapy: Often effective
• Surgery decisions: May choose bilateral mastectomy even for unilateral cancer
• Targeted therapy: Active area of research

Clinical Trials

• BRCA carriers often eligible for targeted therapy trials
• Discuss with oncology team
• Research advancing rapidly

Family Implications

Inheritance Pattern

• Autosomal dominant: 50% chance to pass to each child
• Affects both males and females (though risks differ)
• Males can pass mutation even though their cancer risk is lower

Testing Family Members

• First-degree relatives should consider testing
• Parents, siblings, children at 50% risk
• Extended family may benefit from testing
• Cascade testing can identify at-risk relatives

Emotional Considerations

• Testing positive can be emotionally challenging
• Support resources available
• Genetic counseling includes emotional support
• Support groups for BRCA carriers

Prevalence

• Ashkenazi Jews: ~1% carry 5382insC specifically
• Polish population: Relatively common founder mutation
• General population: Rare (~1 in 400-500 overall for any BRCA1 mutation)

Testing Considerations

Direct-to-Consumer Testing Limitations

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

Clinical Testing

• Full gene sequencing identifies all mutations
• Large rearrangement analysis included
• Insurance often covers if criteria met
• Genetic counseling should accompany testing

Frequently Asked Questions

Does having this mutation mean I'll definitely get cancer?

No. While the 5382insC mutation significantly increases cancer risk (55-70% for breast, 40-45% for ovarian), many carriers never develop cancer. Enhanced screening can catch cancers early when they're most treatable, and risk-reducing surgeries can dramatically lower risk. Knowledge empowers prevention.

Should I tell my family members?

This is a personal decision, but sharing information can be life-saving. First-degree relatives have a 50% chance of carrying the same mutation. Many families choose to share results so relatives can make informed decisions about their own testing and screening. A genetic counselor can help you navigate these conversations.

I'm a man - does this affect me?

Yes, though differently. Male BRCA1 carriers have modestly increased risk of breast cancer (still low absolute risk), prostate cancer, and possibly pancreatic cancer. Importantly, you can pass the mutation to your children. Your daughters would have the same high breast/ovarian cancer risks as any female carrier.

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. NCCN Guidelines. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2.2024.
3. Struewing JP, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997;336(20):1401-1408.