Abstract
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. To determine the risks of breast cancer associated with germline variants in cancer predisposition genes. 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. Breast cancer risk conferred by pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes. 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. 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.
Highlights
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
These include high-penetrance BRCA1 and BRCA2 breast and ovarian cancer genes; mismatch repair genes; high-penetrance CDH1, PTEN, STK11, and TP53 genes that are associated with hereditary diffuse gastric cancer as well as Cowden disease, Peutz-Jeghers syndrome, and Li-Fraumeni syndrome, respectively; and genes associated with moderate risks of breast cancer (2-fold to 5-fold), such as CHEK2 and ATM.[7,8]
The frequency of variants in each of the panel genes among individuals qualifying for clinical genetic testing remains to be defined, and the risks of breast and other cancers associated with variants in many panel genes are not established
Summary
Study Population Study participants included a nationwide sample of 65 057 women with breast cancer referred for hereditary cancer genetic testing by Ambry Genetics Inc between March 15, 2012, and June 30, 2016. Demographic, clinical history, and family history of cancer information (eTable 1 and eTable 2 in the Supplement) were collected from test requisition forms, clinic notes, and pedigrees provided by ordering clinicians at the time of testing. Phenotype Data A potential limitation of this study is the quality and quantity of the clinical history information collected for the paneltested patients. The variant frequencies and breast cancer risk estimates from this study were derived from probands and were not dependent on family history information. A review of a random sample of 1200 breast and ovarian cancer patient intake forms was conducted. The accuracy of personal cancer history was greater than 97% (eMethods in the Supplement)
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