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

Int J Mol Sci. 2016 Dec 21;17(12):2145. doi: 10.3390/ijms17122145.


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.

Keywords: BRCA1; breast cancer; next generation sequencing; partial intron retention; splicing mutation.

MeSH terms

  • Adult
  • Aged
  • BRCA1 Protein / genetics*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Female
  • Humans
  • Introns
  • Male
  • Mutation*
  • Pedigree
  • RNA Splicing*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism


  • BRCA1 Protein
  • BRCA1 protein, human
  • RNA, Messenger