Prevalence of MUTYH germline variants in Pediatric and Adolescent/Young Adult Patients with a Brain Tumor

Background Germline pathogenic and likely pathogenic variants (PV/LPV) in MutY DNA Glycosylase (MUTYH), a key gene in the Base Excision Repair (BER) pathway, are classically linked to MUTYH-associated polyposis (MAP) and colorectal cancer. Emerging evidence suggests that MUTYH variants, particularly monoallelic ones, may contribute to susceptibility to other malignancies, including central nervous system (CNS) tumors. Methods We retrospectively analyzed 378 pediatric and adolescent/young adult (AYA) patients (222 males, 156 females) with CNS tumors diagnosed between 2011 and 2025. All patients underwent clinical exome sequencing, which included analysis of the MUTYH gene. Tumors were classified according to the WHO CNS 5th edition. Variant inheritance was determined by trio-based next-generation sequencing (NGS) and classified according to ACMG guidelines. Results MUTYH variants were found in 15/378 patients: PV/LPV were detected in 11 patients (2.9%) and variants of uncertain significance (VUSs) in 4 (1.1%). One patient carried biallelic variants p.Glu452del and p.Tyr76*; while ten patients had monoallelic variants: p.Tyr179Cys (n = 4), p.Gly368Asp (n = 5) and p.Arg242His (n = 1). The prevalence of the rs34612342 and rs36053993 variants was 1.1% and 1.3%, respectively. The Sixty percent of cases with a MUTYH variant reported a positive family history for cancer. In this large single-institution cohort of pediatric and AYA patients with a diagnosis of a CNS tumor, 4.0% of patients carried germline MUTYH variants, predominantly monoallelic pathogenic or likely pathogenic substitutions. Conclusions Our findings support the inclusion of MUTYH in multigene germline testing panels for pediatric CNS tumors and warrant further investigation into its mechanistic and clinical significance as a low-penetrance susceptibility factor in neuro-oncogenesis.