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The Clinical Significance of Unknown Sequence Variants in BRCA Genes

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 co...

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Autores principales: Calò, Valentina, Bruno, Loredana, Paglia, Laura La, Perez, Marco, Margarese, Naomi, Gaudio, Francesca Di, Russo, Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837329/
https://www.ncbi.nlm.nih.gov/pubmed/24281179
http://dx.doi.org/10.3390/cancers2031644
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author Calò, Valentina
Bruno, Loredana
Paglia, Laura La
Perez, Marco
Margarese, Naomi
Gaudio, Francesca Di
Russo, Antonio
author_facet Calò, Valentina
Bruno, Loredana
Paglia, Laura La
Perez, Marco
Margarese, Naomi
Gaudio, Francesca Di
Russo, Antonio
author_sort Calò, Valentina
collection PubMed
description 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.
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spelling pubmed-38373292013-11-22 The Clinical Significance of Unknown Sequence Variants in BRCA Genes Calò, Valentina Bruno, Loredana Paglia, Laura La Perez, Marco Margarese, Naomi Gaudio, Francesca Di Russo, Antonio Cancers (Basel) Review 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. MDPI 2010-09-10 /pmc/articles/PMC3837329/ /pubmed/24281179 http://dx.doi.org/10.3390/cancers2031644 Text en © 2010 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0/ This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Review
Calò, Valentina
Bruno, Loredana
Paglia, Laura La
Perez, Marco
Margarese, Naomi
Gaudio, Francesca Di
Russo, Antonio
The Clinical Significance of Unknown Sequence Variants in BRCA Genes
title The Clinical Significance of Unknown Sequence Variants in BRCA Genes
title_full The Clinical Significance of Unknown Sequence Variants in BRCA Genes
title_fullStr The Clinical Significance of Unknown Sequence Variants in BRCA Genes
title_full_unstemmed The Clinical Significance of Unknown Sequence Variants in BRCA Genes
title_short The Clinical Significance of Unknown Sequence Variants in BRCA Genes
title_sort clinical significance of unknown sequence variants in brca genes
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837329/
https://www.ncbi.nlm.nih.gov/pubmed/24281179
http://dx.doi.org/10.3390/cancers2031644
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