Mutation detection rates associated with specific selection criteria for BRCA1/2 testing in 1854 high-risk families: A monocentric Italian study

Abstract Background BRCA mutation screening is frequently offered on the basis of the fulfillment of empirical selection criteria, thought to be indicative of a genetic predisposition to breast/ovarian cancer (BrCa/OvCa). This study aimed to evaluate, in a large cohort of BrCa/OvCa families, the mutation detection rate (DR) associated with specific clinical features and the relative performance of the employed selection criteria. Methods BRCA gene analysis was performed on 1854 family probands. The Fisher exact test was used to compare the DRs associated with different clinical features. In a subset of families fulfilling only mutually exclusive criteria, odds ratios and 95% CI were estimated to test the relative effectiveness of each criterion. Results The overall DR was 29.3%. Among BrCa-only families, the DRs were significantly higher in the presence of early-onset compared with late-onset cases, and of bilateral compared with unilateral cases. In families with bilateral cases, ages at diagnosis of both the first and second tumour were significantly lower in mutation carriers. In families fulfilling mutually exclusive criteria, OvCa was the best predictor of BRCA mutations, with DRs (range: 31.8%–80.0%) significantly higher compared with the other criteria. Conversely, isolated early-onset BrCa and three or more late-onset BrCa displayed significantly lower predictive values (7.9% and 7.2%, respectively). Conclusions The observed estimates, albeit confirming a DR above 10% for most of the considered criteria, highlighted some relevant differences among them. Such differences should be taken into account in the identification of patients who might benefit from genetic counselling and subsequent testing.