Abstract
BACKGROUND: Breast cancer (BC) is the most prevalent cancer globally. Carriers of pathogenic variants in high- or moderate-penetrance genes, have an increased risk of developing hereditary BC (HBC). While, MUTYH is known to be associated with hereditary colonic polyposis and colorectal carcinoma, its role in BC is controversial. This study investigated the genetic cause of HBC in an Iranian family with a history of multiple cancer cases. METHODS: Clinical examination and exome sequencing (ES) was performed in a patient suffering from invasive ductal carcinoma from a family with several cases of different types of cancer. The pathogenicity of detected variants was done based on American Collage of Medical Genetics (ACMG) and Sanger sequencing was carried out for its validation. Furthermore, we performed a comprehensive review of the literature. RESULTS: Here, a pathogenic variant (p. A287Pfs*32) was identified in the MUTYH gene in mono-allelic status in four BC patients. However, this variant was previously reported as the cause of MutYH-associated polyposis (MAP) in homozygous status. The review of literature showed that the frequency of MUTYH mutation in BC patients population is in a range of 0.3-5.6%. CONCLUSION: In this study, a heterozygous pathogenic variant in the MUTYH gene was identified as the possible cause of BC in a multi-cancer family using ES. While the potential association between mono-allelic MUTYH mutations and an elevated risk of BC remains controversial, these findings highlight the necessity for a careful interpretation when assessing the role of MUTYH mutations in BC risk.