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Usefulness and Limitations of Comprehensive Characterization of mRNA Splicing Profiles in the Definition of the Clinical Relevance of BRCA1/2 Variants of Uncertain Significance
Highly penetrant variants of BRCA1/2 genes are involved in hereditary predisposition to breast and ovarian cancer. The detection of pathogenic BRCA variants has a considerable clinical impact, allowing appropriate cancer-risk management. However, a major drawback is represented by the identification...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468917/ https://www.ncbi.nlm.nih.gov/pubmed/30832263 http://dx.doi.org/10.3390/cancers11030295 |
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author | Gelli, Elisa Colombo, Mara Pinto, Anna Maria De Vecchi, Giovanna Foglia, Claudia Amitrano, Sara Morbidoni, Valeria Imperatore, Valentina Manoukian, Siranoush Baldassarri, Margherita Lo Rizzo, Caterina Catania, Lorenza Frullanti, Elisa Tagliafico, Enrico Cortesi, Laura Spaggiari, Federica Mencarelli, Maria Antonietta Trevisson, Eva Radice, Paolo Renieri, Alessandra Ariani, Francesca |
author_facet | Gelli, Elisa Colombo, Mara Pinto, Anna Maria De Vecchi, Giovanna Foglia, Claudia Amitrano, Sara Morbidoni, Valeria Imperatore, Valentina Manoukian, Siranoush Baldassarri, Margherita Lo Rizzo, Caterina Catania, Lorenza Frullanti, Elisa Tagliafico, Enrico Cortesi, Laura Spaggiari, Federica Mencarelli, Maria Antonietta Trevisson, Eva Radice, Paolo Renieri, Alessandra Ariani, Francesca |
author_sort | Gelli, Elisa |
collection | PubMed |
description | Highly penetrant variants of BRCA1/2 genes are involved in hereditary predisposition to breast and ovarian cancer. The detection of pathogenic BRCA variants has a considerable clinical impact, allowing appropriate cancer-risk management. However, a major drawback is represented by the identification of variants of uncertain significance (VUS). Many VUS potentially affect mRNA splicing, making transcript analysis an essential step for the definition of their pathogenicity. Here, we characterize the impact on splicing of ten BRCA1/2 variants. Aberrant splicing patterns were demonstrated for eight variants whose alternative transcripts were fully characterized. Different events were observed, including exon skipping, intron retention, and usage of de novo and cryptic splice sites. Transcripts with premature stop codons or in-frame loss of functionally important residues were generated. Partial/complete splicing effect and quantitative contribution of different isoforms were assessed, leading to variant classification according to Evidence-based Network for the Interpretation of Mutant Alleles (ENIGMA) consortium guidelines. Two variants could be classified as pathogenic and two as likely benign, while due to a partial splicing effect, six variants remained of uncertain significance. The association with an undefined tumor risk justifies caution in recommending aggressive risk-reduction treatments, but prevents the possibility of receiving personalized therapies with potential beneficial effect. This indicates the need for applying additional approaches for the analysis of variants resistant to classification by gene transcript analyses. |
format | Online Article Text |
id | pubmed-6468917 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-64689172019-04-23 Usefulness and Limitations of Comprehensive Characterization of mRNA Splicing Profiles in the Definition of the Clinical Relevance of BRCA1/2 Variants of Uncertain Significance Gelli, Elisa Colombo, Mara Pinto, Anna Maria De Vecchi, Giovanna Foglia, Claudia Amitrano, Sara Morbidoni, Valeria Imperatore, Valentina Manoukian, Siranoush Baldassarri, Margherita Lo Rizzo, Caterina Catania, Lorenza Frullanti, Elisa Tagliafico, Enrico Cortesi, Laura Spaggiari, Federica Mencarelli, Maria Antonietta Trevisson, Eva Radice, Paolo Renieri, Alessandra Ariani, Francesca Cancers (Basel) Article Highly penetrant variants of BRCA1/2 genes are involved in hereditary predisposition to breast and ovarian cancer. The detection of pathogenic BRCA variants has a considerable clinical impact, allowing appropriate cancer-risk management. However, a major drawback is represented by the identification of variants of uncertain significance (VUS). Many VUS potentially affect mRNA splicing, making transcript analysis an essential step for the definition of their pathogenicity. Here, we characterize the impact on splicing of ten BRCA1/2 variants. Aberrant splicing patterns were demonstrated for eight variants whose alternative transcripts were fully characterized. Different events were observed, including exon skipping, intron retention, and usage of de novo and cryptic splice sites. Transcripts with premature stop codons or in-frame loss of functionally important residues were generated. Partial/complete splicing effect and quantitative contribution of different isoforms were assessed, leading to variant classification according to Evidence-based Network for the Interpretation of Mutant Alleles (ENIGMA) consortium guidelines. Two variants could be classified as pathogenic and two as likely benign, while due to a partial splicing effect, six variants remained of uncertain significance. The association with an undefined tumor risk justifies caution in recommending aggressive risk-reduction treatments, but prevents the possibility of receiving personalized therapies with potential beneficial effect. This indicates the need for applying additional approaches for the analysis of variants resistant to classification by gene transcript analyses. MDPI 2019-03-01 /pmc/articles/PMC6468917/ /pubmed/30832263 http://dx.doi.org/10.3390/cancers11030295 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Gelli, Elisa Colombo, Mara Pinto, Anna Maria De Vecchi, Giovanna Foglia, Claudia Amitrano, Sara Morbidoni, Valeria Imperatore, Valentina Manoukian, Siranoush Baldassarri, Margherita Lo Rizzo, Caterina Catania, Lorenza Frullanti, Elisa Tagliafico, Enrico Cortesi, Laura Spaggiari, Federica Mencarelli, Maria Antonietta Trevisson, Eva Radice, Paolo Renieri, Alessandra Ariani, Francesca Usefulness and Limitations of Comprehensive Characterization of mRNA Splicing Profiles in the Definition of the Clinical Relevance of BRCA1/2 Variants of Uncertain Significance |
title | Usefulness and Limitations of Comprehensive Characterization of mRNA Splicing Profiles in the Definition of the Clinical Relevance of BRCA1/2 Variants of Uncertain Significance |
title_full | Usefulness and Limitations of Comprehensive Characterization of mRNA Splicing Profiles in the Definition of the Clinical Relevance of BRCA1/2 Variants of Uncertain Significance |
title_fullStr | Usefulness and Limitations of Comprehensive Characterization of mRNA Splicing Profiles in the Definition of the Clinical Relevance of BRCA1/2 Variants of Uncertain Significance |
title_full_unstemmed | Usefulness and Limitations of Comprehensive Characterization of mRNA Splicing Profiles in the Definition of the Clinical Relevance of BRCA1/2 Variants of Uncertain Significance |
title_short | Usefulness and Limitations of Comprehensive Characterization of mRNA Splicing Profiles in the Definition of the Clinical Relevance of BRCA1/2 Variants of Uncertain Significance |
title_sort | usefulness and limitations of comprehensive characterization of mrna splicing profiles in the definition of the clinical relevance of brca1/2 variants of uncertain significance |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468917/ https://www.ncbi.nlm.nih.gov/pubmed/30832263 http://dx.doi.org/10.3390/cancers11030295 |
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