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Original Investigation
April 13, 2017

Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer

Author Affiliations
  • 1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
  • 2Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
  • 3Huntsman Cancer Institute, Department of Dermatology, University of Utah, Salt Lake City
  • 4Department of Clinical Diagnostics, Ambry Genetics Inc, Aliso Viejo, California
  • 5Now, Division of Genetics and Genomics, Department of Pediatrics, University of California–Irvine
JAMA Oncol. Published online April 13, 2017. doi:10.1001/jamaoncol.2017.0424
Key Points

Question  Which genes on hereditary cancer multigene testing panels are associated with high or moderate risks of breast cancer among patients qualifying for clinical genetic testing?

Findings  In a case-control study of 65 057 patients with breast cancer, inherited pathogenic variants in PALB2 were associated with high risks of breast cancer, and variants in CHEK2, ATM, BARD1, and RAD51D were associated with moderate risks of breast cancer. Variants in MRE11A, RAD50, NBN, BRIP1, RAD51C, MLH1, and NF1 were not associated with increased risks of breast cancer.

Meaning  Although pathogenic variants in several panel genes confer increased risks of breast cancer and may qualify patients for increased cancer surveillance, variants in several other cancer panel genes may not predispose to breast cancer.


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.