A Novel ATRIP Mutation Detected in an Iranian Family with Familial Clustering of Breast Cancer: A Case Report

<b>Purpose:</b> ATRIP (ATR-interacting protein) is a critical partner of ATR (ataxia telangiectasia and Rad3-related). The ATR-ATRIP heterodimer plays an essential role in initiating homologous recombination repair (HRR) during replication stress and inducing double-stranded DNA breaks following unresolved stalled replication forks. Our team recently identified <i>ATRIP</i> as a novel breast cancer susceptibility gene candidate through whole-exome sequencing (WES) of familial breast cancer patients and healthy controls from the Polish founder population, with subsequent validation in both Polish and British cohorts. In the present study, we report for the first time the detection of a novel deleterious mutation in <i>ATRIP</i> among several members of an Iranian family with clustering of breast cancer who were negative for mutations in the already known breast cancer risk genes. <b>Methods:</b> Six family members underwent germline DNA testing by WES, following initial negative results from multigene panel testing. Candidate variants were confirmed by Sanger sequencing and assessed according to ACMG guidelines. <b>Results:</b> We detected a novel <i>ATRIP</i> frameshift mutation (NM_130384.3:c.1033delC) in four of six family members that were tested, including two individuals affected with breast cancer. No pathogenic variants were found in other known cancer susceptibility genes. <b>Conclusions:</b> This is the first report of a deleterious <i>ATRIP</i> mutation in an Iranian family with familial breast cancer, suggesting a potential role of <i>ATRIP</i> in hereditary breast cancer. Further studies are required to confirm the role of ATRIP in breast cancer susceptibility, refine risk assessment, and evaluate potential personalized therapeutic strategies. In the interim, genetic counseling for ATRIP mutation carriers should proceed with caution, given current limitations in clinical interpretation.