Protein-Truncating and Rare Missense Variants in Breast Cancer Risk Genes: Association With Disease Risk

Breast Cancer Association Consortium Study

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In a study reported in The New England Journal of Medicine, members of the international Breast Cancer Association Consortium (BCAC) identified the risk of disease associated with germline protein-truncating and rare missense variants of putative susceptibility genes in a large population of breast cancer cases and controls from BCAC studies.

The entire study population consisted of 53,461 women in a control cohort, and 60,466 women with invasive (90.3%) or in situ tumors (6.9%) or tumors of unknown invasiveness (2.7%) from 44 BCAC studies, including 14 enriched with patients with family history of breast cancer. The population-based analysis included 48,826 patients with invasive or in situ breast cancer and 50,703 controls from 30 BCAC population-based studies (ie, studies with no oversampling of patients with family history of breast cancer) performed in individuals from 25 predominately European countries.

Sequencing of germline DNA was performed on a panel of 34 putative susceptibility genes. Risks of breast cancer overall and for tumor subtypes were assessed for protein-truncating variants and rare missense variants (those with population frequency < 0.001) of these genes.

Findings for Protein-Truncating Variants

Protein-truncating variants in five genes were associated with risk of breast cancer overall, with a P value less than .0001: ATM (odds ratio [OR] = 2.10), BRCA1 (OR = 10.57), BRCA2 (OR = 5.85), CHEK2 (OR = 2.54; OR = 2.66 for c.1100delC variant and 2.13 for other variants), and PALB2 (OR = 5.02).

Evidence of an association with increased risk of breast cancer overall was found for variants in seven additional genes: BARD1 (OR = 2.09, P = .00098), RAD51C (OR = 1.93, P = .0070), RAD51D (OR = 1.80, P = .018), PTEN (OR = 2.25, P = .10), NF1 (OR = 1.76, P = .068), TP53 (OR = 3.06, P = .17), and MSH6 (OR = 1.96, P = .013).

Of the remaining 22 genes (ABRAXAS1, AKT1, BABAM2, BRIP1, CDH1, EPCAM, FANCC, FANCM, GEN1, MEN1, MLH1, MRE11, MSH2, MUTYH, NBN, PIK3CA, PMS2, RAD50, RECQL, RINT1, STK11, and XRCC2), all but 3 (AKT1, MSH2, and STK11, none with statistically significant ORs) had an upper limit of the 95% confidence interval (CI) of the odds ratio of < 2.0 (no estimated moderate or high risk).


  • Evidence of strong or more moderate association with increased overall breast cancer risk was found for protein-truncating variants of 12 of 34 putative risk genes.
  • Evidence of increased risk was found for aggregated rare missense variants of six genes.

Among the 12 genes with evidence of an association with breast cancer overall, odd ratios were higher for estrogen receptor (ER)-positive vs ER-negative disease for variants in ATM (2.33 vs 1.01, P = .00055 for difference) and CHEK2 (2.67 vs 1.64, P = 3.6 × 10−5 for difference). CHEK2 also had evidence of an association with ER-negative, non–triple-negative breast cancer (OR = 2.53, 95% CI = 1.75–3.67), but not with triple-negative disease.

Odds ratios were higher for ER-negative vs ER-positive disease for variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D (P < .05 for all). Of these genes, three had a stronger association with triple-negative disease vs ER-negative, non–triple-negative disease: BARD1 (P = .044 for difference), BRCA1 (P = 9.6 × 10−17), and BRCA2 (P = 7.8 × 10−5). For variants in BRCA1, BRCA2, and PALB2, odds ratios were higher for invasive vs in situ tumors; for ATM and CHEK2, odds ratios were similar for invasive vs in situ tumors.

Findings for Missense Variants

Evidence of an association with breast cancer overall for aggregated rare missense variants was found for six genes: CHEK2 (OR = 1.42, P = 2.5 × 10−11; P = 2.9 × 10−18 in population from all 44 studies), ATM (OR  = 1.06, P = .051; P = .0010 in all studies), TP53 (OR = 1.10, P = .32; P = .00080 in all studies), BRCA1 (OR = 1.11, P = .010; P = .027 in all studies), CDH1 (OR = 1.10, P = .096; P = .042 in all studies), and RECQL (OR = 1.12, P = .047; P = .036 in all studies). CHEK2 (P = 9.1 × 10−5 for difference) and CDH1 (P = .012 for difference) exhibited a stronger association with ER-positive vs ER-negative disease and BRCA1 (P = .01 for difference) had a stronger association with ER-negative vs ER-positive breast cancer. Odds ratios decreased with increasing age for BRCA1 (P = .0026), CHEK2 (P = .00022), and TP53 (P = .00023).

The investigators concluded, “The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling.”

Disclosure: The study was funded by European Union Horizon 2020 programs, Wellcome Trust, and Cancer Research UK. For full disclosures of the study authors, visit

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