Background: Multiple-gene germline sequencing panels are increasingly used to assess hereditary cancer risk, yet the magnitude of OC risk is not well defined for many genes on clinically available panels. Methods: 95,561 women were tested clinically for hereditary cancer risk with a panel of 25 genes: APC, ATM, BARD1, BMPR1A, BRCA1/2, BRIP1, CDH1, CDK4, CHEK2, MLH2, MSH2, MSH6, MYH, NBN, P14ARF, P16, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, and TP53. Patients who had single- or founder-site testing, or prior BRCA1/2 testing, were excluded. Multivariable regression analysis was used to examine the association between pathogenic/suspected pathogenic mutations and personal OC history (Hx) (dependent variable). Independent variables were age, personal/family cancer Hx, and ancestry. Odds ratios (OR) with 95% confidence intervals (CI) excluding 1.0 were considered significant. Results: Mutations were detected in 6,775/95,561 (7%) patients, of which 3,007 (44%) were in BRCA1/2 and 3,768 (56%) in other genes. A significant association with personal OC Hx was found for ATM, BRCA1, BRCA2, BRIP1, MLH1, MSH2, MSH6, NBN, STK11, RAD51C and RAD51D (Table). Conclusions: Among nearly 100,000 women tested clinically for hereditary cancer risk, multiple-gene sequencing detected OC-associated mutations in 11 genes. Gene-specific estimates ranged from two (ATM, BRIP1, NBN, MSH2, MSH6) to > 10 (BRCA1, STK11) fold elevation in OC risk. These results inform the estimation of OC risk with mutations in 25 clinically tested genes.

*Could not be estimated