Results of two large case–control studies that analyzed the associations between a number of putative cancer susceptibility genes and breast cancer risk are published on 20 January 2021 in The New England Journal of Medicine. The international study included samples from 60,466 women with breast cancer and 53,461 controls from 25 countries participating in the Breast Cancer Association Consortium (BCAC) studies, while the Cancer Risk Estimates Related to  Susceptibility (CARRIERS) consortium study included 28 genes among 32,247 women with breast cancer and 32,544 controls from the US.

Variants in 8 genes — BRCA1, BRCA2, PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2 — had a significant association with breast cancer risk in both studies. Additionally, there was a significant association for variants in MSH6 in the international study only and for variants in CDH1 in the US study only. These studies help to establish the genes that confer a predisposition to breast cancer. Distribution of mutations among women with breast cancer was different from the distribution among controls.

Protein-truncating variants of several genes in the panel associate strongly with breast cancer

Leila Dorling served as lead author for the investigators in the BCAC of the University of Cambridge, Strangeways Research Laboratory in Cambridge, UK.1 Their case–control study aimed to define the most clinically useful genes that should appear in panels by determining the risk of breast cancer associated with these genes and their variants. They also estimated the odds ratios (ORs) for breast cancer overall and for specific tumour sub-types that are associated with protein-truncating variants and rare missense variants in these genes.

The Consortium found that protein-truncating variants in the ATM, BRCA1, BRCA2, CHEK2, and PALB2 genes were associated with a risk of breast cancer overall (p < 0.0001), as were protein-truncating variants in the BARD1, RAD51C, RAD51D, and TP53 genes (p < 0.05; Bayesian false-discovery probability < 0.05).

However, the upper limit of the 95% confidence interval (CI) of the OR for breast cancer overall was <2.0 for the protein-truncating variants in 19 of the remaining 25 genes.

Regarding protein-truncating variants of the ATM and CHEK2 genes, the ORs were higher in oestrogen receptor (ER)–positive disease as compared to ER-negative disease, whereas ORs were higher for ER-negative than for ER-positive disease for protein-truncating variants of the BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D genes. Rare missense variants (in aggregate) of ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall (p < 0.001). The authors determined that missense variants of BRCA1, BRCA2, and TP53, (in aggregate), which would be classified as pathogenic by standard criteria, were associated with a risk of breast cancer overall that was similar to that of protein-truncating variants.

Risk estimates for breast cancer in the general population are provided

In the same issue of The New England Journal of Medicine, Chunling Hu from the Mayo Clinic in Rochester, USA and co-investigators employed a population-based case–control approach to provide estimates of the prevalence and risk of breast cancer in the overall US population that is associated with pathogenic variants in known breast cancer–predisposition genes.2

Using a custom multigene amplicon-based panel containing 28 cancer-predisposition genes, sequencing was performed for the identification of germline pathogenic variants. Then the associations were assessed between pathogenic variants in each gene and the risk of breast cancer.

The investigators identified pathogenic variants in 12 established breast cancer–predisposition genes that were detected in 5.03% women with breast cancer and in 1.63% of controls. Among these variants, those identified in BRCA1 and BRCA2 were associated with a high risk of breast cancer (OR 7.62; 95% CI 5.33-11.27; p < 0.001 and OR 5.23; 95% CI 4.09-6.77; p < 0.001), respectively, whereas a moderate risk of breast cancer was associated with pathogenic variants in PALB2 (OR 3.83; 95% CI 2.68-5.63; p < 0.001).

An increased risk for ER–negative breast cancer and triple-negative breast cancer was found to associate with pathogenic variants in BARD1, RAD51C, and RAD51D, while an increased risk of ER–positive breast cancer associated with pathogenic variants in ATM, CDH1, and CHEK2.

The investigators determined that pathogenic variants of 16 of the candidate breast cancer–predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, did not associate with an increased risk of breast cancer.


The authors of both studies underscored the crucial importance of determining the risk of breast cancer that is associated with genes included in panels currently used in clinical management, as well as the germline pathogenic variants and protein-truncating variants of these genes.

Dorling et al. concluded that their study findings defined the genes that are most clinically useful for inclusion in panels for the prediction of breast cancer risk and advocated that their results may guide screening, as well as prevention with risk-reducing surgery or medication, in accordance with national guidelines.

Additional information to inform cancer testing and screening and improve clinical management strategies was provided in the study by Hu et al., which provided estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer–predisposition genes. The authors noted that most studies involve women at high risk, whereas their population-based cohort indicated the risk for women in the general US population with inherited pathogenic variants in cancer-predisposing genes.

Additional conclusions to these results were drawn in accompanied editorial3, where Steven A. Narod echoed the importance of identifying the genes most likely to identify women at risk of breast cancer but also addressed the practical implications of the results of these studies. He noted that both studies implicated variants of 8 genes (BRCA1, BRCA2, PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2) and found significant associations between these and the risk of breast cancer risk.

However, according to Dr. Narod both studies also found that majority of the genes tested did not show a significant association with disease, which impacts clinicians who are expanding the use of gene-panel testing to include unaffected women at moderate risk of breast cancer due to family history. He pondered whether clinicians should begin discussing each gene shown to have an association with breast cancer risk in these studies with patients before offering a panel test and whether the genes not showing an association with disease should be removed from the panels.

He addressed the practical utility of this information by discussing management options. Using women with a variant in CHEK2 or ATM as an example, he explained that women with these mutations are ER-positive and may be candidates for anti-oestrogen therapies; however, chemoprevention studies have not been performed in women who carry mutations in CHEK2 or ATM and the uptake of tamoxifen is low, even among carriers of a BRCA1 or BRCA2 mutation. Therefore, since neither preventive salpingo-oophorectomy nor preventive mastectomy is recommended, the majority of women with a mutation in ATM or CHEK2 are managed by screening alone.

The editorial comments that these studies are useful in establishing the genes that confer a predisposition to breast cancer and those that do not, but does not advise on the elimination of genes from the panels currently used in screening.

The study by Dorling et al. was supported by the European Union Horizon 2020 research and innovation programmes BRIDGES, B-CAST, the Wellcome Trust, and Cancer Research UK. The study by Hu et al. was funded by the US National Institutes of Health and the Breast Cancer Research Foundation. 


  1. Breast Cancer Association Consortium. Breast Cancer Risk Genes – Association Analysis in More than 113,000 Women. N Engl J Med 2021;384:428-439. doi: 10.1056/NEJMoa1913948.
  2. Hu C, Hart SN, Gnanaolivu R, et al. A Population-Based Study of Genes Previously Implicated in Breast Cancer. N Engl J Med 2021;384:440-451. doi:  10.1056/NEJMoa2005936.
  3. Narod SA. Which Genes for Hereditary Breast Cancer. N Engl J Med 2021; 384:471-473. doi: 10.1056/NEJMe2035083.