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

Abstract

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 Finder 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.

Comprehensive Mutational Analysis of the BRCA1-Associated DNA Helicase and Tumor-Suppressor FANCJ/BACH1/BRIP1

“…Likewise, FA-associated FANCJ clinical mutations fail to restore ICL resistance, consistent with the role of FANCJ enzyme activity in ICL repair processing (14). While other pathogenic variants that disrupt FANCJ enzyme function, expression, or splicing have been identified (17,20,22,23), the majority of FANCJ sequence changes remain unclassified, thereby limiting clinical utility.…”

Comparison of whole exome sequencing in circulating tumor cells of primitive and metastatic nasopharyngeal carcinoma

“…Zhao ( 46 ) reported that MLH1 , MSH2 , MSH6 and PMS1 are present in stage II and III colorectal cancer patients. Velázquez et al ( 47 ) found that BRIP1 gene mutations occurred in inherited breast cancer patients. It was also reported that the association between MSH6 and BRIP1 variants are relevant to oxidative DNA damage in triple negative breast patients ( 48 ).…”