Is a heterozygous mutation (a mutation in one of the two copies of a gene) linked to an increased risk of breast cancer?

Heterozygous Mutations and Breast Cancer Risk

Yes, heterozygous mutations in certain genes are strongly linked to increased breast cancer risk, with BRCA1/2 mutations conferring the highest risk (50-85% lifetime risk) among the high-penetrance genes. 1

High-Penetrance Gene Mutations

Heterozygous mutations in high-penetrance genes significantly increase breast cancer risk:

• BRCA1: 65-82% lifetime risk of breast cancer 1, 2

  • Tumors often triple-negative with high histologic grade 1
  • 39-48% lifetime risk of ovarian cancer 1, 2

• BRCA2: 45-85% lifetime risk of breast cancer 1

  • Tumors more similar to sporadic breast cancers 1
  • 11-23% lifetime risk of ovarian cancer 1
  • Higher risk of male breast cancer (5-10%) 1

• Other high-penetrance genes (each conferring up to 80% lifetime risk) 1:

  • TP53: Associated with Li-Fraumeni syndrome
  • PTEN: Associated with Cowden syndrome (85% lifetime risk)
  • CDH1: 39% lifetime risk of lobular breast cancer
  • STK11: 32% risk by age 60

Moderate-Penetrance Gene Mutations

Heterozygous mutations in moderate-penetrance genes confer approximately a twofold increase in breast cancer risk 1:

• CHEK2
• BRIP1
• ATM: ~25% lifetime risk, mostly ER-positive cancers 3
• PALB2
• RAD51C: Recently identified as potentially high-risk 1

Clinical Implications

1. Genetic Testing Criteria 1:

   • Three or more breast/ovarian cancer cases (at least one <50 years)
   • Two breast cancer cases <40 years
   • Male breast cancer and ovarian/early-onset female breast cancer
   • Ashkenazi Jewish ancestry with breast cancer <60 years
   • Young-onset bilateral breast cancer
   • Breast and ovarian cancer in the same patient

2. Risk Management 2:

   • Enhanced surveillance starting at younger ages (25-30)
   • Monthly self-examinations
   • Clinical breast examinations twice yearly
   • Annual mammography and MRI
   • Consideration of risk-reducing surgeries
   • Chemoprevention options

Important Considerations

• Heterozygous mutations account for <25% of all breast cancer cases 1
• The underlying cause of >70% of familial breast cancer cases remains unexplained 1
• Double heterozygosity (mutations in two different genes) can occur but is rare 4
• The specific risk conferred by a particular mutation may diverge from general estimates due to high allelic heterogeneity 1
• Genetic testing should be performed after genetic counseling and informed consent 1

Pitfalls to Avoid

1. Not considering family history: Even without identified mutations, a strong family history of early-onset breast cancer significantly increases risk 5
2. Focusing only on BRCA1/2: Less than one-third of early-onset familial breast cancers are BRCA1/2-related 5
3. Overlooking moderate-penetrance genes: Though individually less common, collectively they contribute to breast cancer risk 1
4. Assuming all mutations have equal impact: The specific mutation location and type affect cancer risk and characteristics 1

Genetic testing with extended gene panels is now recommended for all women diagnosed with breast cancer at age 65 or below to guide personalized management 3.