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Cancers 2019, 11(3), 295;

Usefulness and Limitations of Comprehensive Characterization of mRNA Splicing Profiles in the Definition of the Clinical Relevance of BRCA1/2 Variants of Uncertain Significance

Medical Genetics, University of Siena, 53100 Siena, Italy
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), 20133 Milan, Italy
Genetica medica Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy
Department of Woman and Child Health, University of Padova, 35128 Padova, Italy
Istituto di Ricerca Pediatrica, IRP, Città della Speranza, 35129 Padova, Italy
Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), 20133 Milan, Italy
Department of Medical and Surgical Science, Center for Genome Research, University of Modena and Reggio Emilia, 41125 Modena, Italy
Department of Oncology and Haematology, Azienda Ospedaliero-Universitaria Policlinico, University of Modena and Reggio Emilia, 41124 Modena, Italy
Author to whom correspondence should be addressed.
These authors equally contributed to the manuscript.
Received: 11 January 2019 / Revised: 18 February 2019 / Accepted: 20 February 2019 / Published: 1 March 2019
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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. View Full-Text
Keywords: splicing; BRCA; mRNA analysis; VUS splicing; BRCA; mRNA analysis; VUS

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Gelli, E.; Colombo, M.; Pinto, A.M.; De Vecchi, G.; Foglia, C.; Amitrano, S.; Morbidoni, V.; Imperatore, V.; Manoukian, S.; Baldassarri, M.; Lo Rizzo, C.; Catania, L.; Frullanti, E.; Tagliafico, E.; Cortesi, L.; Spaggiari, F.; Mencarelli, M.A.; Trevisson, E.; Radice, P.; Renieri, A.; Ariani, F. Usefulness and Limitations of Comprehensive Characterization of mRNA Splicing Profiles in the Definition of the Clinical Relevance of BRCA1/2 Variants of Uncertain Significance. Cancers 2019, 11, 295.

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