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

作者：Esposito Maria Valeria; Nunziato Marcella; Starnone Flavio; Telese Antonella; Calabrese Alessandra; D'Aiuto Giuseppe; Pucci Pietro; D'Aiuto Massimiliano; Baralle Francisco; D'Argenio Valeria^*; Salvatore Francesco^*

来源：International Journal of Molecular Sciences, 2016, 17(12): 2145.

DOI：10.3390/ijms17122145

• breast cancer
• BRCA1
• next generation sequencing
• splicing mutation
• partial intron retention

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.

• 出版日期2016-12