Estimating the likelihood of carrying pathogenic variants in the breast and ovarian cancer susceptibility genes: a validation of the BOADICEA model

Abstract

Abstract Background: The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), now a part of CanRisk, is a comprehensive risk prediction tool for breast and/or ovarian cancer (BOC) with a high accuracy to predict the likelihood of carrying pathogenic variants (PVs) in BRCA1 and BRCA2. BOADICEA version 6 also includes PVs in PALB2, CHEK2, ATM, BARD1, RAD51C and RAD51D, but the accuracy of its predictions remains to be investigated. Methods: The study included 2,033 individuals counselled at clinical genetics departments in Denmark on suspicion of hereditary susceptibility to BOC. All counselees underwent comprehensive genetic testing by next generation sequencing of BRCA1, BRCA2, PALB2, CHEK2, ATM, BARD1, RAD51C and RAD51D. Predicted likelihoods of PVs were obtained from BOADICEA v6.1.0. The accuracy of predictions was examined by calibration using the observed-to-expected ratio (O/E) and by discrimination using the area under the receiver-operating characteristics curve (AUC). Results: BOADICEA remained well-calibrated after addition of the additional genes. Thus, the O/E was 1.07 (95% CI 0.94-1.22) for all genes in the model combined. At sub-categories of predicted likelihood, the model performed well with only limited misestimation at the extremes of predicted likelihood. The ability to discriminate between carriers and non-carriers of PVs was acceptable with an AUC of 0.70 (95% CI 0.66-0.74), although discrimination was better for BRCA1 and BRCA2 (AUC 0.79) than for the other genes (AUC 0.59). Conclusion: BOADICEA remains a valid decision-making aid for determining which individuals to offer comprehensive genetic testing on the suspicion of hereditary susceptibility to BOC.