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Cancers 2010, 2(3), 1644-1660; doi:10.3390/cancers2031644

The Clinical Significance of Unknown Sequence Variants in BRCA Genes

1 Department of Surgery and Oncology, Regional Reference Center for the Biomolecular Characterization and Genetic Screening of Hereditary Tumors, University of Palermo, Via del Vespro 127, 90127 Palermo, Italy 2 Department of Medical Biotechnologies and Legal Medicine, University of Palermo, Palermo, Italy Both authors have contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 29 June 2010 / Revised: 8 July 2010 / Accepted: 31 August 2010 / Published: 10 September 2010
(This article belongs to the Special Issue Epidemiologic Research and Cancer)
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Germline mutations in BRCA1/2 genes are responsible for a large proportion of hereditary breast and/or ovarian cancers. Many highly penetrant predisposition alleles have been identified and include frameshift or nonsense mutations that lead to the translation of a truncated protein. Other alleles contain missense mutations, which result in amino acid substitution and intronic variants with splicing effect. The discovery of variants of uncertain/unclassified significance (VUS) is a result that can complicate rather than improve the risk assessment process. VUSs are mainly missense mutations, but also include a number of intronic variants and in-frame deletions and insertions. Over 2,000 unique BRCA1 and BRCA2 missense variants have been identified, located throughout the whole gene (Breast Cancer Information Core Database (BIC database)). Up to 10–20% of the BRCA tests report the identification of a variant of uncertain significance. There are many methods to discriminate deleterious/high-risk from neutral/low-risk unclassified variants (i.e., analysis of the cosegregation in families of the VUS, measure of the influence of the VUSs on the wild-type protein activity, comparison of sequence conservation across multiple species), but only an integrated analysis of these methods can contribute to a real interpretation of the functional and clinical role of the discussed variants. The aim of our manuscript is to review the studies on BRCA VUS in order to clarify their clinical relevance.
Keywords: BRCA genes; variant; integrated models; oncogenetic counseling BRCA genes; variant; integrated models; oncogenetic counseling
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Calò, V.; Bruno, L.; La Paglia, L.; Perez, M.; Margarese, N.; Di Gaudio, F.; Russo, A. The Clinical Significance of Unknown Sequence Variants in BRCA Genes. Cancers 2010, 2, 1644-1660.

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