Breast Cancer Susceptibility Genes: Putting the Pieces Together

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With the widespread use of multigene panels for germline genetic testing, understanding the cancer risks associated with pathogenic or likely pathogenic variants (ie, mutations) has become increasingly necessary. To identify which genes are breast cancer susceptibility genes, population studies that compare the frequency of mutations in women with unselected breast cancer (cases) with that in women without cancer (controls) are optimal. Most previous studies drew breast cancer cases from genetic clinics, which can overestimate the frequency of mutations in patients who typically have stronger family histories of cancer. Even among mutation carriers, it is known that a strong family history of cancer increases the risk for breast and other cancers.

Nadine M. Tung, MD

Nadine M. Tung, MD

Comparing Population-Based Studies

The study recently reported in The New England Journal of Medicine by Hu et al,1 reviewed in this issue of The ASCO Post, thus provides useful information about which genes are breast cancer susceptibility genes. This population-based case-control study conducted in the United States by the CARRIERS consortium included approximately 32,000 women with unselected breast cancer and 32,000 women without cancer; the investigators evaluated 28 potential breast cancer susceptibility genes.

It is best to interpret the results of the CARRIERS study with those from another population-based case-control study concurrently published in The New England Journal of Medicine from the Breast Cancer Association Consortium (BCAC)2—also reviewed in this issue of The ASCO Post. The BCAC study was a larger international study that included 113,000 women and tested for 34 potential breast cancer risk genes. Of the studies included in the BCAC analysis, 30 used unselected breast cancer cases (population-based studies), as did the CARRIERS study, whereas 14 were enriched for cases in women with a family history of breast cancer (family-based studies). The population-based studies in the BCAC analysis included almost 100,000 women with approximately 49,000 cases and 51,000 controls.

Focus on Specific Genes

Both the CARRIERS and BCAC population–based studies confirmed that BRCA1, BRCA2, PALB2, ATM, and CHEK2 are indeed breast cancer risk genes. BRCA1, BRCA2, and PALB2 confer a high risk of breast cancer (odds ratio [OR] = ~ > 4), whereas ATM and CHEK2 (truncating mutations) are moderate-risk genes (OR = ~ 2–2.5). Risk estimates for mutations in the rare, syndrome-related genes (eg, TP53, PTEN, CDH1, STK11) are particularly difficult to establish, given the rarity of the mutations and because many individuals with these mutations are tested through genetics clinics due to family histories of cancer and are thus excluded from these types of population-based studies.

Three other genes showed a significant association with breast cancer. In the BCAC study, these genes were BARD1, RAD51C, and RAD51D, with odds ratios of 2.09 (95% confidence interval [CI] = 1.35–3.23), 1.93 (95% CI = 1.2–3.11), and 1.8 (95% CI = 1.11–2.93), respectively. Of note, although the odds ratios for mutations in these three genes were not significant in the CARRIERS study, they fell within the 95% confidence interval reported in the larger BCAC study. In addition, the CARRIERS study did find an increased risk of estrogen receptor–negative breast cancer with mutations in BARD1 and RAD51D, even though the risks of breast cancer overall were not significantly increased. In the BCAC study, there was also a modest association with breast cancer risk for two other genes: Lynch gene MSH6 (OR = 1.96, 95% CI = 1.15–3.33, P = .013) and NF1 (OR = 1.76, 95% CI = 0.96–3.21, P = .068). Again, the odds ratios in the CARRIERS study fell within these 95% confidence intervals.

Of note, neither study found evidence of an increased risk of breast cancer with mutations in NBN (including c.657_661del5), RAD50, or BRIP1. Previously, the listed Slavic NBN founder mutation had been reported to be associated with a moderate increase in breast cancer risk.

If genes like RAD51C and RAD51D are ultimately accepted as breast cancer risk genes, the associated risk threshold to be clinically important will need to be established. Previously, mutations that result in a doubling of cancer risk (ie, relative risk ≥ 2) have generally been viewed to have sufficient clinical utility to justify inclusion in multigene panels.

Clinical Implications

There are potentially important clinical implications for identifying breast cancer susceptibility genes. For women not diagnosed with breast cancer, identifying mutations in these genes provides opportunities for enhanced screening and cancer prevention. Women with mutations in moderate-risk genes such as ATM and CHEK2 have a lifetime risk of breast cancer that exceeds 20%, making them eligible for surveillance by breast magnetic resonance imaging (MRI). Both the CARRIERS and BCAC studies confirm the association of ATM and CHEK2 mutations with estrogen receptor–positive breast cancer, providing rationale for the use of risk-reducing endocrine therapy, even if prospective data confirming the clinical utility of this strategy are lacking.

Among women with breast cancer, data about the risk of contralateral breast cancer with mutations in genes other than BRCA1 and BRCA2 are generally lacking. Some data exist for the frameshift mutation CHEK2 1100delC, for which the risk of contralateral breast cancer is approximately threefold higher.3 More data are needed about how low-risk genetic variants (ie, polygenic risk score), family cancer history, and age at diagnosis affect the risk of contralateral breast cancer among patients with mutations in moderate-risk breast cancer genes like ATM and CHEK2. Although robust data are lacking, for those with mutations in BRCA1/2, PALB2, ATM, or CHEK2 who opt for breast-conserving therapy, an annual breast MRI is recommended.4

Mutations in these genes may also increase the risk of other cancers. For example, mutations in RAD51C and RAD51D increase the risk of ovarian cancer such that salpingo-oophorectomy should be considered. CHEK2 mutations increase the risk of colorectal cancer, and ATM mutations increase the risk of pancreatic cancer. MSH6 mutations increase the risk of Lynch syndrome–related cancers.5 Finally, mutations in these genes may also have important reproductive implications; inheritance of biallelic mutations in ATM causes ataxia-telangiectasia, and such inheritance in BRCA2, PALB2, or RAD51C causes Fanconi anemia.

Dr. Tung is Director of Breast Medical Oncology and the Cancer Genetics and Prevention Program at Beth Israel Deaconess Medical Center, Boston.

DISCLOSURE: Dr. Tung has received research funding from AstraZeneca and has received institutional research funding from Myriad Genetics.


1. Hu C, Hart SN, Gnanaolivu R, et al: A population-based study of genes previously implicated in breast cancer. N Engl J Med 384:440-451, 2021.

2. Dorling L, Carvalho S, Allen J, et al, for the Breast Cancer Association Consortium: Breast cancer risk genes: Association analysis in more than 113,000 women. N Engl J Med 384:428-439, 2021.

3. Weischer M, Nordestgaard BG, Pharoah P, et al: CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer. J Clin Oncol 30:4308-4316, 2012.

4. Tung NM, Boughey JC, Pierce LJ, et al: Management of hereditary breast cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline. J Clin Oncol 38:2080-2106, 2020.

5. Daly MB, Pal T, Berry MP, et al: National Comprehensive Cancer Network Clinical Practice Guidelines in Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, version 2.2021. Available at Accessed March 1, 2021.

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