Unraveling the molecular effect of a rare missense mutation in BRIP1 associated with inherited breast cancer

Mol Carcinog. 2019 Jan;58(1):156-160. doi: 10.1002/mc.22910. Epub 2018 Sep 22.


BRIP1 is a component of the Fanconi Anemia/BRCA pathway responsible for DNA reparation via helicase activity. Some heterozygous variants in BRIP1 could contribute to Hereditary Breast Cancer through a defective DNA repair. The clinical utility of BRIP1 mutations in a familial cancer context is compromised by the conflicting interpretation of "variants of uncertain significance" (VUS). Defining the clinical significance of variants identified in genetic tests is a major challenge; therefore, studies that evaluate the biological effect of these variants are definitely necessary. To contribute to this purpose, we have characterized the variant c.550G>T of BRIP1, a missense mutation with little evidence about its pathogenicity. Since Human Splicing FinderTM predicts the creation of a new exonic splicing enhancer site we decided to perform cDNA analysis revealing that the c.550G>T mutation located in exon 6 led to an aberrant transcript causing exon 5 skipping. Our results demonstrate that the c.550G>T BRIP1 variant disrupts normal splicing, causing exon 5 skipping. Considering that the exon 5 encodes the helicase domain of BRIP1, it is expected an alteration of the function. This finding enhances the interpretation of this VUS, suggesting a potential pathogenic effect.

Keywords: BRIP1; aberrant splicing; germline mutations; hereditary breast and ovarian cancer.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology*
  • Fanconi Anemia Complementation Group Proteins / genetics*
  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Middle Aged
  • Mutation, Missense*
  • Pedigree
  • Prognosis
  • RNA Helicases / genetics*


  • Fanconi Anemia Complementation Group Proteins
  • BRIP1 protein, human
  • RNA Helicases

Supplementary concepts

  • Breast Cancer, Familial