BARD1, RAD51D, and MSH6 gene variants increase breast cancer risk, according to a large-scale sequencing analysis presented at the 2016 San Antonio Breast Cancer Symposium.

Gene panels are potentially effective methods for germline mutation screening of predisposition genes, said lead study author Fergus J. Couch, PhD, of the Mayo Clinic in Rochester, Minnesota.

But “risks, if any, of breast and other cancers associated with pathogenic variants in several panel genes are not defined,” he said.

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As more testing occurs, the list of variants of unknown clinical significance (VUS) continues to grow.

Further complicating matters, the strength of associations between pathogenic gene variants and breast cancer risk—or the risk of other cancers—remains ambiguous in many cases, with “wide confidence intervals,” Dr Couch noted.

To better characterize the breast cancer risks associated with inherited (germline) cancer-predisposition genes, Dr Couch and his team collaborated with Ambry Genetics, a gene testing lab, to assess 38,326 Caucasian patients with breast cancer diagnosed between 2012 and 2016.

“Pathogenic variants from germline genetic testing of 21 known and candidate breast cancer predisposition genes were evaluated,” he said. “Frequency of variants in breast cancer cases was compared with frequency of variants in the ExAC Non-Finn European non-TCGA control group.”

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The 3 most frequent panel genes identified among patients with breast cancer were ATM, CHEK2, and PALB2, supporting the recent identification of ATM as a breast cancer gene and PALB2 as a high-risk breast cancer gene. Associations between breast cancer and previously-known highly-penetrant genes like TP53, PTEN, and CDH1 were confirmed.

BARD1, RAD51D, and MSH6—previously considered variants of unknown breast cancer significance—were found to be moderate-risk breast cancer genes, Dr Couch reported.


  1. Couch FJ, Hu C, Lilyquist J, et al. Breast cancer risks associated with mutations in cancer predisposition genes identified by clinical genetic testing of 60,000 breast cancer patients. Paper presented at: 39th San Antonio Breast Cancer Symposium; Dec 2016; San Antonio, TX.