Breast Cancer Risk Genes — Association Analysis in More than 113,000 Women
Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.
However,
We found strong evidence of an association with breast cancer risk (Bayesian false-discovery probability, <0.05) for protein-truncating variants in 9 genes, with a P value of less than 0.0001 for 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) and a P value of less than 0.05 for the other 4 genes (BARD1, RAD51C, RAD51D, and TP53).
None of the other 25 genes in the panel had a Bayesian false-discovery probability of less than 0.10. Of note, 19 genes had an upper limit of the 95% confidence interval of the odds ratio of less than 2.0, with 2.0 representing a proposed threshold for “pathogenic, moderate risk alleles”9; we therefore conclude that these genes are not informative for the prediction of breast cancer risk. We confirmed that missense variants in BRCA1, BRCA2, and TP53 that would be classified as pathogenic according to clinical guidelines are indeed associated with clinically significant risks. We also found that rare missense variants in CHEK2 overall, as well as variants in specific domains in ATM, are associated with moderate risk.
The summary:
Variants in 8 genes — BRCA1, BRCA2, PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2 — had a significant association with breast cancer risk.
