Hereditary Breast Cancer Beyond BRCA Genes
Beyond BRCA1 and BRCA2, hereditary breast cancer can be caused by mutations in high-penetrance genes (TP53, PTEN, CDH1, STK11), moderate-penetrance genes (CHEK2, ATM, PALB2, BRIP1), and several low-penetrance genes that collectively contribute to breast cancer risk. 1
High-Penetrance Breast Cancer Susceptibility Genes
TP53: Associated with Li-Fraumeni Syndrome, conferring up to 25% risk of breast cancer by age 74. Also associated with sarcoma, brain tumors, adrenocortical carcinoma, and leukemia 1
PTEN: Associated with PTEN Hamartoma Tumor Syndrome/Cowden Syndrome, with up to 85% lifetime risk of breast cancer. Also linked to nonmedullary thyroid cancer and endometrial cancer 1
CDH1: Associated with Hereditary Diffuse Gastric Cancer, with approximately 39% lifetime risk of lobular breast cancer. Also linked to diffuse gastric cancer and colorectal cancer 1
STK11: Associated with Peutz-Jeghers Syndrome, with approximately 32% risk of breast cancer by age 60. Also linked to GI cancers, pancreatic cancer, and sex-cord stromal tumors 1
Moderate-Penetrance Breast Cancer Susceptibility Genes
CHEK2: One of the most common moderate-risk genes, conferring approximately a twofold increase in breast cancer risk. Particularly prevalent in certain populations, with recurrent mutations suggesting founder effects 1, 2
ATM: Associated with intermediate risk of breast cancer. Mutations in this gene are involved in DNA repair mechanisms 1, 2
PALB2: Partner and localizer of BRCA2, with increasing recognition of its importance in hereditary breast cancer. Recurrent mutations have been identified in certain populations, suggesting founder effects 1, 2
BRIP1: BRCA1-interacting protein, associated with moderate breast cancer risk 1
Additional Breast Cancer Susceptibility Genes
RAD51C and RAD51D: Potentially high-risk cancer predisposition genes in breast/ovarian cancer families 1
BARD1: Emerging evidence supports its role in hereditary breast cancer 1, 2
NF1: Associated with neurofibromatosis type 1 and increased breast cancer risk 3
RAD50: Involved in DNA repair mechanisms and associated with breast cancer risk 1
XRCC2: Implicated in DNA repair and breast cancer susceptibility 1
Clinical Implications
Despite identification of multiple susceptibility genes, >70% of familial breast cancer cases remain unexplained genetically 1
Multigene panel testing is now recommended when multiple genes could explain an inherited cancer syndrome, as this approach is more cost-effective and comprehensive 4
Recurrent mutations in specific populations (such as in PALB2 and CHEK2) may represent founder effects, which can be important for targeted screening in certain ethnic groups 2
Genetic testing should be considered for individuals with:
- Breast cancer diagnosed at age ≤45 years
- Breast cancer diagnosed at age ≤50 years with family history
- Personal history of multiple primary breast cancers
- Male breast cancer
- Family history of breast and/or ovarian cancer
- Ashkenazi Jewish ancestry with breast, ovarian, or pancreatic cancer 4
Important Considerations and Pitfalls
A negative BRCA1/2 test does not rule out hereditary breast cancer risk if family history remains suggestive - consider testing for other susceptibility genes 4
Interpretation of variants of uncertain significance remains challenging and requires expertise 4
Penetrance varies significantly between high-risk genes (up to 80% lifetime risk) and moderate-risk genes (approximately twofold increase in risk) 1
Regular reassessment of family history is essential as new cancer events may alter risk assessment and testing recommendations 4
Polygenic risk (cumulative effect of multiple low-penetrance alleles) is increasingly recognized as an important contributor to breast cancer susceptibility 3, 5