Are there other familial breast cancer gene mutations besides BRCA (Breast Cancer Gene)?

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Multiple Genes Beyond BRCA1/2 Are Associated with Familial Breast Cancer

Yes, there are several other familial breast cancer gene mutations besides BRCA1 and BRCA2 that significantly increase breast cancer risk, including TP53, PTEN, CDH1, STK11, CHEK2, ATM, BRIP1, and PALB2. 1

High-Penetrance Genes

High-penetrance genes confer a substantial lifetime risk of breast cancer (50-85%):

  • BRCA1 and BRCA2: Account for approximately 20% of familial breast cancer cases 1
  • TP53: Associated with Li-Fraumeni Syndrome, conferring a 25% risk of breast cancer by age 74 1
  • PTEN: Associated with PTEN Hamartoma Tumor Syndrome/Cowden Syndrome with an 85% lifetime risk 1
  • CDH1: Associated with Hereditary Diffuse Gastric Cancer and a 39% lifetime risk of lobular breast cancer 1
  • STK11: Associated with Peutz-Jeghers Syndrome and a 32% risk by age 60 1

Moderate-Penetrance Genes

These genes confer a moderate (approximately 2-fold) increase in breast cancer risk:

  • CHEK2: One of the more common moderate-risk genes 1
  • ATM: Associated with increased breast cancer susceptibility 1
  • BRIP1: Functionally related to BRCA genes 1
  • PALB2: Partner and localizer of BRCA2 1
  • RAD51C: More recently identified as a potential high-risk predisposition gene in breast/ovarian cancer families 1

Clinical Implications

Despite the identification of these genes, it's important to note that:

  • More than 70% of familial breast cancer cases remain unexplained by known genetic mutations 1
  • Mutations in high-penetrance genes (BRCA1, BRCA2, TP53, PTEN, CDH1, and STK11) collectively account for only 5-10% of breast cancer cases overall 1
  • Multiple low-penetrance genetic variants likely contribute to breast cancer risk in a polygenic fashion 1

Testing Considerations

Genetic testing should be considered when:

  • There are three or more breast/ovarian cancer cases in a family, with at least one diagnosed before age 50 1
  • Two breast cancer cases diagnosed before age 40 1
  • Male breast cancer with early-onset female breast cancer 1
  • Breast and ovarian cancer in the same patient 1

Associated Cancer Risks

Different gene mutations are associated with different cancer risk profiles:

  • BRCA1: High risk of ovarian cancer (37-62%) 1
  • BRCA2: Moderate risk of ovarian cancer (11-23%) and increased risk of male breast cancer (6%) 1
  • TP53: Increased risk of sarcomas, brain tumors, adrenocortical carcinoma, and leukemia 1
  • PTEN: Associated with thyroid cancer and endometrial cancer 1
  • CDH1: Associated with diffuse gastric cancer and colorectal cancer 1
  • STK11: Associated with GI cancers and pancreatic cancer 1

Emerging Research

Research continues to identify additional genetic factors contributing to breast cancer risk. Current evidence suggests there may be at least one more major breast cancer susceptibility gene beyond those currently identified 2. Additionally, multiple genetic polymorphisms with individually small effects may act together to increase risk in a polygenic fashion 1.

References

1
Guideline

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Dr.Oracle Medical Advisory Board & Editors, 2025

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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