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BRCA1 p.Val1688del Is a Deleterious Mutation That Recurs in Breast and Ovarian Cancer Families From Northeast Italy

Sandro Malacrida, Simona Agata, Monia Callegaro, Cinzia Casella, Daniela Barana, Maria C. Scaini, Siranoush Manoukian, Cristina Oliani, Paolo Radice, Monica Barile, Chiara Menin, Emma D'Andrea, Marco Montagna

From the Department of Oncology and Surgical Sciences, Oncology Section; Istituto Oncologico Veneto - IRCCS, Padua; U.O.A. ULSS 5 Ovest Vicentino, Vinicenza; Fondazione IRCCS Istituto Nazionale Tumori; FIRC Institute of Molecular Oncology Foundation; and the European Institute of Oncology, Milan, Italy

Corresponding author: Marco Montagna, PhD, Istituto Oncologico Veneto, UOC Immunologia e Diagnostica Molecolare Oncologica, via Gattamelata, 64; I-35128 Padova, Italy; e-mail: montagna{at}unipd.it

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.

Supported by Ministero dell'Università e della Ricerca (MIUR), Ministero della Sanità - Programma Straordinario Ricerca Oncologica, Alleanza Contro il Cancro, Fondazione Cassa di Risparmio di Padova e Rovigo, and fellowships from "Accademia Nazionale dei Lincei" (S.A.) and Fondazione Italiana per la Ricerca sul Cancro (M.C.S).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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