BRCA1 p.Val1688del Is a Deleterious Mutation That Recurs in Breast and Ovarian Cancer Families From Northeast Italy
- 1 January 2008
- journal article
- research article
- Published by American Society of Clinical Oncology (ASCO) in Journal of Clinical Oncology
- Vol. 26 (1), 26-31
- https://doi.org/10.1200/jco.2007.13.2118
Abstract
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. 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. 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. 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.Keywords
This publication has 21 references indexed in Scilit:
- Classification of missense variants of unknown significance inBRCA1based on clinical and tumor informationHuman Mutation, 2007
- Determination of Cancer Risk Associated with Germ Line BRCA1 Missense Variants by Functional AnalysisCancer Research, 2007
- Genetic and Histopathologic Evaluation ofBRCA1andBRCA2DNA Sequence Variants of Unknown Clinical SignificanceCancer Research, 2006
- Genetic analysis of BRCA1 ubiquitin ligase activity and its relationship to breast cancer susceptibilityHuman Molecular Genetics, 2006
- Application of Embryonic Lethal or Other Obvious Phenotypes to Characterize the Clinical Significance of Genetic Variants Found in Trans with Known Deleterious MutationsCancer Research, 2005
- Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutralJournal of Medical Genetics, 2005
- Analysis of missense variation in human BRCA1 in the context of interspecific sequence variationJournal of Medical Genetics, 2004
- A Full-Likelihood Method for the Evaluation of Causality of Sequence Variants from Family DataAmerican Journal of Human Genetics, 2003
- Identification of families with hereditary breast and ovarian cancer for clinical and mammographic surveillance: the Modena Study Group proposalBreast Cancer Research and Treatment, 1999
- A Strong Candidate for the Breast and Ovarian Cancer Susceptibility Gene BRCA1Science, 1994