title: A Novel Pathogenic BRCA1 Splicing Variant Produces Partial Intron Retention in the Mature Messenger RNA.
abstract: 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 theBRCA1orBRCA2genes. The identification ofBRCA1/BRCA2mutations 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 newBRCA1variant discovered in a breast cancer patient duringBRCA1/2screening 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 inBRCA1intron 21; and consequently the partial retention of 156 bp of intron 21 in the patient's transcript; which demonstrates that this novelBRCA1mutation 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.
authors.affiliation: CEINGE-Biotecnologie Avanzate, via Gaetano Salvatore 486, 80145 Naples, Italy. espositomari@ceinge.unina.it.
authors.forename: Maria Valeria
authors.initials: MV
authors.lastname: Esposito
authors.affiliation: CEINGE-Biotecnologie Avanzate, via Gaetano Salvatore 486, 80145 Naples, Italy. nunziato@ceinge.unina.it.|Department of Movement Sciences and Wellness (DiSMEB), University of Naples Parthenope, via Medina 40, 80133 Naples, Italy. nunziato@ceinge.unina.it.
authors.forename: Marcella
authors.initials: M
authors.lastname: Nunziato
authors.affiliation: CEINGE-Biotecnologie Avanzate, via Gaetano Salvatore 486, 80145 Naples, Italy. starnone@ceinge.unina.it.
authors.forename: Flavio
authors.initials: F
authors.lastname: Starnone
authors.affiliation: CEINGE-Biotecnologie Avanzate, via Gaetano Salvatore 486, 80145 Naples, Italy. telesea@ceinge.unina.it.
authors.forename: Antonella
authors.initials: A
authors.lastname: Telese
authors.affiliation: CEINGE-Biotecnologie Avanzate, via Gaetano Salvatore 486, 80145 Naples, Italy. alessandra.underforty@gmail.com.|Department of Senology, Istituto Nazionale Tumori-IRCCS Fondazione Pascale, via Mariano Semmola, 52, 80131 Naples, Italy. alessandra.underforty@gmail.com.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Calabrese
authors.affiliation: Department of Senology, Istituto Nazionale Tumori-IRCCS Fondazione Pascale, via Mariano Semmola, 52, 80131 Naples, Italy. giuseppe@daiuto.org.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Aiuto
authors.affiliation: CEINGE-Biotecnologie Avanzate, via Gaetano Salvatore 486, 80145 Naples, Italy. pucci@unina.it.
authors.forename: Pietro
authors.initials: P
authors.lastname: Pucci
authors.affiliation: Department of Senology, Istituto Nazionale Tumori-IRCCS Fondazione Pascale, via Mariano Semmola, 52, 80131 Naples, Italy. massimiliano.daiuto@gmail.com.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: D'Aiuto
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Science Park, Padriciano 99, 34149 Trieste, Italy. baralle@icgeb.org.
authors.forename: Francisco
authors.initials: F
authors.lastname: Baralle
authors.affiliation: CEINGE-Biotecnologie Avanzate, via Gaetano Salvatore 486, 80145 Naples, Italy. dargenio@ceinge.unina.it.|Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, via Sergio Pansini 5, 80131 Naples, Italy. dargenio@ceinge.unina.it.
authors.forename: Valeria
authors.initials: V
authors.lastname: D'Argenio
authors.affiliation: CEINGE-Biotecnologie Avanzate, via Gaetano Salvatore 486, 80145 Naples, Italy. salvator@unina.it.|Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, via Sergio Pansini 5, 80131 Naples, Italy. salvator@unina.it.|IRCCS-Fondazione SDN, via Emanuele Gianturco 113, 80143 Naples, Italy. salvator@unina.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Salvatore
mesh_terms: D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D007438:Introns; D008297:Male; D009154:Mutation; D010375:Pedigree; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D012333:RNA, Messenger
keywords: BRCA1; breast cancer; next generation sequencing; partial intron retention; splicing mutation