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Int. J. Mol. Sci. 2016, 17(12), 2145;

A Novel Pathogenic BRCA1 Splicing Variant Produces Partial Intron Retention in the Mature Messenger RNA

CEINGE-Biotecnologie Avanzate, via Gaetano Salvatore 486, 80145 Naples, Italy
Department of Movement Sciences and Wellness (DiSMEB), University of Naples Parthenope, via Medina 40, 80133 Naples, Italy
Department of Senology, Istituto Nazionale Tumori–IRCCS Fondazione Pascale, via Mariano Semmola, 52, 80131 Naples, Italy
International Centre for Genetic Engineering and Biotechnology, Science Park, Padriciano 99, 34149 Trieste, Italy
Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, via Sergio Pansini 5, 80131 Naples, Italy
IRCCS-Fondazione SDN, via Emanuele Gianturco 113, 80143 Naples, Italy
Authors to whom correspondence should be addressed.
Academic Editor: William Chi-shing Cho
Received: 28 October 2016 / Revised: 30 November 2016 / Accepted: 14 December 2016 / Published: 21 December 2016
(This article belongs to the Special Issue Next-Generation Sequencing for Clinical Application)
Full-Text   |   PDF [2586 KB, uploaded 21 December 2016]   |  


About 10% of all breast cancers arise from hereditary mutations that increase the risk of breast and ovarian cancers; and about 25% of these are associated with the BRCA1 or BRCA2 genes. The identification of BRCA1/BRCA2 mutations can enable physicians to better tailor the clinical management of patients; and to initiate preventive measures in healthy carriers. The pathophysiological significance of newly identified variants poses challenges for genetic counseling. We characterized a new BRCA1 variant discovered in a breast cancer patient during BRCA1/2 screening by next-generation sequencing. Bioinformatic predictions; indicating that the variant is probably pathogenetic; were verified using retro-transcription of the patient’s RNA followed by PCR amplifications performed on the resulting cDNA. The variant causes the loss of a canonic donor splice site at position +2 in BRCA1 intron 21; and consequently the partial retention of 156 bp of intron 21 in the patient’s transcript; which demonstrates that this novel BRCA1 mutation plays a pathogenetic role in breast cancer. These findings enabled us to initiate appropriate counseling and to tailor the clinical management of this family. Lastly; these data reinforce the importance of studying the effects of sequence variants at the RNA level to verify their potential role in disease onset. View Full-Text
Keywords: breast cancer; BRCA1; next generation sequencing; splicing mutation; partial intron retention breast cancer; BRCA1; next generation sequencing; splicing mutation; partial intron retention

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Esposito, M.V.; Nunziato, M.; Starnone, F.; Telese, A.; Calabrese, A.; D’Aiuto, G.; Pucci, P.; D’Aiuto, M.; Baralle, F.; D’Argenio, V.; Salvatore, F. A Novel Pathogenic BRCA1 Splicing Variant Produces Partial Intron Retention in the Mature Messenger RNA. Int. J. Mol. Sci. 2016, 17, 2145.

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