# The Genetic and Molecular Analyses of Rare Candidate Germline BRIP1/FANCJ Variants Implicated in Hereditary Breast and Ovarian Cancers

## TL;DR

This study identifies three BRIP1 gene variants that may increase the risk of breast and ovarian cancers.

## Contribution

The study confirms three BRIP1 variants as clinically relevant in hereditary breast and ovarian cancers.

## Key findings

- Three BRIP1 variants (p.Thr266Met, p.Pro696Leu, p.Thr997ArgfsTer61) were predicted to be damaging.
- These variants conferred cellular sensitivity to mitomycin C and cisplatin.
- The variants were found in cancer cases but not in population-matched controls.

## Abstract

Five rare variants in BRIP1/FANCJ, initially identified in ovarian cancer (OC) or breast cancer (BC) cases by the adult hereditary cancer clinics, were investigated for their candidacy as clinically relevant variants. These variants were investigated genetically in a population exhibiting genetic drift and molecularly assayed for biological impact. Using in silico tools, population-based genetic databases and other resources, three of the five reported BRIP1 variants were likely to be damaging: c.797C>T; p.Thr266Met, c.2087C>T; p.Pro696Leu and c.2990_2993delCAAA; p.Thr997ArgfsTer61. The carrier frequencies ranged from 0 to 0.7% in ancestry-defined cancer groups comprising 47 OC families, 49 hereditary breast and ovarian cancer syndrome families, 142 hereditary breast cancer syndrome families, 435 sporadic OC cases and 563 sporadic BC cases and 0–0.2% in 1025 population-matched controls. Multiple carriers of the these variants were identified in additional population-matched cancer cases. Of the five reported BRIP1 variants, p.Thr266Met, p.Pro696Leu and c.2990_2993delCAAA; p.Thr997ArgfsTer61, which were predicted to be damaging, conferred cellular sensitivity to mitomycin C and cisplatin unlike p.Ser139Ala and p.Ala406Ser. Collectively, our investigation implicates BRIP1 c.797C>T; p.Thr266Met, c.2087C>T; p.Pro696Leu and c.2990_2993delCAAA; p.Thr997ArgfsTer61 as deleterious variants in OC and BC.