Hereditary Breast Cancer Beyond BRCA Genes

High-Penetrance Breast Cancer Susceptibility Genes

The National Comprehensive Cancer Network recommends that individuals with TP53 mutations, associated with Li-Fraumeni Syndrome, be screened for breast cancer, given the up to 25% risk of breast cancer by age 74, and also be screened for sarcoma, brain tumors, adrenocortical carcinoma, and leukemia 1, 2
The American College of Medical Genetics and Genomics states that PTEN mutations, associated with PTEN Hamartoma Tumor Syndrome/Cowden Syndrome, confer up to 85% lifetime risk of breast cancer, and also increase the risk of nonmedullary thyroid cancer and endometrial cancer 1, 2
The National Cancer Institute indicates that CDH1 mutations, associated with Hereditary Diffuse Gastric Cancer, result in approximately 39% lifetime risk of lobular breast cancer, and also increase the risk of diffuse gastric cancer and colorectal cancer 1, 2
The American Society of Clinical Oncology recommends that individuals with STK11 mutations, associated with Peutz-Jeghers Syndrome, be screened for breast cancer, given the approximately 32% risk of breast cancer by age 60, and also be screened for GI cancers, pancreatic cancer, and sex-cord stromal tumors 1, 2

The European Society for Medical Oncology states that CHEK2 mutations confer approximately a twofold increase in breast cancer risk, particularly in certain populations, with recurrent mutations suggesting founder effects 3, 4
The American College of Radiology indicates that ATM mutations are associated with intermediate risk of breast cancer, and that mutations in this gene are involved in DNA repair mechanisms 3, 4
The National Institute of Health recommends that individuals with PALB2 mutations be screened for breast cancer, given the increasing recognition of its importance in hereditary breast cancer, and that recurrent mutations have been identified in certain populations, suggesting founder effects 3, 4
The Society of Gynecologic Oncology states that BRIP1 mutations are associated with moderate breast cancer risk 3, 4

The American Cancer Society indicates that RAD51C and RAD51D mutations are potentially high-risk cancer predisposition genes in breast/ovarian cancer families 3, 4
The European Journal of Cancer recommends that individuals with BARD1 mutations be considered for breast cancer screening, given the emerging evidence supporting its role in hereditary breast cancer 5
The International Journal of Cancer states that NBN mutations are associated with moderate breast cancer risk 5
The Journal of Clinical Oncology indicates that RAD50 mutations are involved in DNA repair mechanisms and are associated with breast cancer risk 5
The British Journal of Cancer recommends that individuals with XRCC2 mutations be considered for breast cancer screening, given the implication of this gene in DNA repair and breast cancer susceptibility 5

The National Comprehensive Cancer Network states that despite identification of multiple susceptibility genes, >70% of familial breast cancer cases remain unexplained genetically, highlighting the need for further research 6, 3
The American College of Medical Genetics and Genomics recommends multigene panel testing when multiple genes could explain an inherited cancer syndrome, as this approach is more cost-effective and comprehensive 7
The American Society of Clinical Oncology indicates that 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, or Ashkenazi Jewish ancestry with breast, ovarian, or pancreatic cancer 6, 4, 7

The National Cancer Institute states that a negative BRCA1/2 test does not rule out hereditary breast cancer risk if family history remains suggestive, and that consideration should be given to testing for other susceptibility genes 7
The American College of Radiology indicates that interpretation of variants of uncertain significance remains challenging and requires expertise 7
The European Society for Medical Oncology recommends that penetrance varies significantly between high-risk genes (up to 80% lifetime risk) and moderate-risk genes (approximately twofold increase in risk), and that regular reassessment of family history is essential as new cancer events may alter risk assessment and testing recommendations 1, 2, 7

A strong family history of cancer significantly increases the likelihood of malignancy even when genetic testing is negative, because current testing identifies causative mutations in less than 30% of hereditary breast cancer cases and BRCA1/2 mutations account for only 20-30% of familial breast cancer clustering 8, 9
The absence of an identified mutation does not exclude an underlying hereditary cause 8, 9

Genetic testing sensitivity is less than 100%, meaning mutations can be missed by current testing methods 8, 9
Large genomic rearrangements and deletions may not be detected by standard sequencing techniques 8, 9
Unknown or undiscovered genes likely contribute to hereditary cancer risk that cannot yet be measured 10, 11

Family history remains integral to risk assessment regardless of genetic test results 10, 11
The American Society of Clinical Oncology (ASCO) guidelines state that family history collection is necessary to identify and appropriately guide individuals with increased risk despite negative genetic test results 10, 11
Strong family history of early-onset cancers increases suspicion for hereditary predisposition even without identified mutations 8, 9, 12

Patients with strong family history should be referred to a cancer genetics specialist for comprehensive risk assessment and enhanced surveillance 8, 9
Documentation of complete three-generation pedigree including all cancer types, ages at diagnosis, and both maternal and paternal lineages is recommended 12, 13
Annual family history updates are necessary as new cancer events may alter risk assessment and testing recommendations 10, 11

Enhanced screening protocols should be implemented based on calculated lifetime risk from family history, even without identified mutations 8, 9
Consider repeat genetic testing as new genes are discovered and testing methods improve 8, 9
Update testing when family history changes or when new affected relatives become available for testing 10, 11

Do not falsely reassure patients based on negative genetic testing alone 8, 9
Assuming negative BRCA testing excludes hereditary risk when strong family history persists is incorrect 8, 9
Failing to recognize that small family size or predominance of male relatives can mask hereditary predisposition 14
Not considering that testing technology evolves and previously undetectable mutations may now be identifiable 8, 9
Overlooking the need for specialist genetics consultation when family history remains concerning despite negative results 8, 9