BRCA1 p.Val1688del is a deleterious mutation that recurs in breast and ovarian cancer families from northeast Italy

Purpose A growing number of sequence changes of unknown clinical significance are being identified in the BRCA1 gene. However, these variants cannot be used for identification and surveillance of at-risk individuals unless their pathogenic role can be demonstrated. The frequency of these variants makes research on this subject a relevant topic in the field of predisposition to breast and ovarian cancers. Herein, we investigate the pathogenicity of the BRCA1 p. Val1688del (c.5181_5183delGTT) variant, which recurs in our population. Patients and Methods Recent studies have drawn attention to different strategies that, if considered singly, do not usually provide sufficient power to firmly state for or against causality, thus forcing to a re-evaluation of the literature on each specific variant. To increase the power of our study, we used a recently described strategy that integrates data from multiple independent evidences. By this approach, we analyzed data from the comprehensive study of 12 breast/ovarian cancer families carrying p. Val1688del. Results We succeeded in integrating five independent evidences of disease causality including segregation, tumor pathology, and evolutionary and epidemiologic data. Under this model, we obtained a final score of 349,000: 1 in favor of disease causality. This result largely matches established cutoffs, and thus is readily translatable into a clear clinical message. Conclusion We show that p. Val1688del is a pathogenic mutation deriving from a common founder. Notably, this study alone increases by 15% the number of BRCA1-positive families in our patients' cohort, thus substantially contributing to explain many of the families wherein prediction of a BRCA1 mutation contrasted with the absence of a molecular recognizable defect.