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. 2017 Sep 1;3(9):1190-1196.
doi: 10.1001/jamaoncol.2017.0424.

Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer

Free PMC article

Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer

Fergus J Couch et al. JAMA Oncol. .
Free PMC article


Importance: Germline pathogenic variants in BRCA1 and BRCA2 predispose to an increased lifetime risk of breast cancer. However, the relevance of germline variants in other genes from multigene hereditary cancer testing panels is not well defined.

Objective: To determine the risks of breast cancer associated with germline variants in cancer predisposition genes.

Design, setting, and participants: A study population of 65 057 patients with breast cancer receiving germline genetic testing of cancer predisposition genes with hereditary cancer multigene panels. Associations between pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes and breast cancer risk were estimated in a case-control analysis of patients with breast cancer and Exome Aggregation Consortium reference controls. The women underwent testing between March 15, 2012, and June 30, 2016.

Main outcomes and measures: Breast cancer risk conferred by pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes.

Results: The mean (SD) age at diagnosis for the 65 057 women included in the analysis was 48.5 (11.1) years. The frequency of pathogenic variants in 21 panel genes identified in 41 611 consecutively tested white women with breast cancer was estimated at 10.2%. After exclusion of BRCA1, BRCA2, and syndromic breast cancer genes (CDH1, PTEN, and TP53), observed pathogenic variants in 5 of 16 genes were associated with high or moderately increased risks of breast cancer: ATM (OR, 2.78; 95% CI, 2.22-3.62), BARD1 (OR, 2.16; 95% CI, 1.31-3.63), CHEK2 (OR, 1.48; 95% CI, 1.31-1.67), PALB2 (OR, 7.46; 95% CI, 5.12-11.19), and RAD51D (OR, 3.07; 95% CI, 1.21-7.88). Conversely, variants in the BRIP1 and RAD51C ovarian cancer risk genes; the MRE11A, RAD50, and NBN MRN complex genes; the MLH1 and PMS2 mismatch repair genes; and NF1 were not associated with increased risks of breast cancer.

Conclusions and relevance: This study establishes several panel genes as high- and moderate-risk breast cancer genes and provides estimates of breast cancer risk associated with pathogenic variants in these genes among individuals qualifying for clinical genetic testing.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Huether and Mss McFarland, Pesaran, LaDuca, and Dolinsky are employees of Ambry Genetics Inc. Dr Chao was employed by Ambry Genetics Inc at the time of the study. No other conflicts were reported.


Figure. Odds Ratio Between Combined Pathogenic Variants in Each Gene and Breast Cancer Among White Women With Breast Cancer and Reference Controls
Exome Aggregation Consortium Non-Finn European data set excluding The Cancer Genome Atlas exomes served as the reference control group. Error bars represent 95% CIs.

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