Protein-truncating variants in 12 genes identified from a panel of more than 100,000 women were associated with increased risk for breast cancer (BC). These findings from the Breast Cancer Association Consortium were published in The New England Journal of Medicine.

Women with (60,466) or without (53,461) breast cancer included in 44 population-based studies were sequenced for 34 established or suspected breast cancer susceptibility genes and compared between groups.

A total of 12 genes with protein-truncating variants significantly associated with risk for breast cancer were identified (odds ratio [OR] range, 1.76 to 10.57; all P £.021). The 5 most highly significant genes included the well-established breast cancer susceptibility genes BRCA1, BRCA2, PALB2, CHEK2, and ATM (OR range, 2.10 to 10.57; all P <.0001).

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In general, ATM and CHEK2 protein-truncating variants are associated with both invasive and in situ tumors and BRCA1, BRCA2, and PALB2 variants are associated with invasive but not in situ tumors.

Stratified by breast cancer type, ATM and CHEK2 protein-truncating variants are more strongly associated with estrogen receptor (ER)-positive disease than with ER-negative disease (P =.00055 and P =3.6×105, respectively). In addition, CHEK2 was also associated with ER-negative, non-triple-negative breast cancer (OR, 2.53; 95% CI, 1.75 to 3.67).

In addition, 6 genes (BRCA1, CHEK2, ATM, TP53, CDH1, and RECQL) had rare missense variants that significantly associated with risk for breast cancer (OR range, 1.06-1.42; all P £.042).

CHEK2 (P =9.1×105) and CDH1 (P =.012) missense variants had a stronger association with ER-positive breast cancer; BRCA1 (P =.01) variants, with ER-negative disease.

These results may have been limited by power, as some variants were extremely rare (eg, TP53 protein-truncating variant [7 patients]).

The study authors concluded that scanning for these protein variants may allow for better breast cancer risk prediction.

Disclosures: Some authors declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original article for a full list of disclosures.


Dorling L, Carvalho S, Allen J, et al. Breast cancer risk genes — association analysis in more than 113,000 women. N Engl J Med. 2021;384(5):428-439. doi:10.1056/NEJMoa1913948

This article originally appeared on Oncology Nurse Advisor