Abstract Background Pathogenic germline variants in MUTYH, a key component of the base excision repair (BER) pathway, are classically associated with MUTYH-associated polyposis and colorectal cancer. Increasing evidence suggests that monoallelic MUTYH variants may confer low-penetrance susceptibility to extraintestinal malignancies, including central nervous system (CNS) tumors. We assessed the prevalence and spectrum of germline MUTYH variants in a large cohort of pediatric and adolescent/young adult (AYA) patients with brain tumors. Methods We retrospectively reviewed 378 consecutive pediatric and AYA patients with primary CNS tumors diagnosed between 2011 and 2025 at a single institution. All patients underwent clinical exome sequencing including MUTYH. Tumors were classified according to the WHO CNS 5th edition. Variant interpretation followed ACMG criteria, and inheritance was assessed by trio-based sequencing when available. Somatic MUTYH alterations were explored by tumor NGS in a subset of cases. Results Germline MUTYH variants were identified in 15/378 patients (4.0%). Pathogenic/likely pathogenic (P/LP) variants were detected in 11/15 (73%), while 4/15 (27%) carried variants of uncertain significance. One patient harbored biallelic P/LP variants (p.Glu452del and p.Tyr76*). Among monoallelic P/LP carriers (n = 10), recurrent founder variants predominated, including p.Tyr179Cys–equivalent substitutions (n = 4) and p.Gly396Asp–equivalent substitutions (n = 5), with an additional p.Arg242His variant (n = 1). A positive family history of cancer was reported in 60% of variant-positive cases. Six patients (40%) also carried additional germline alterations in other cancer-predisposition genes. Conclusions In this single-institution pediatric/AYA CNS tumor cohort, 4.0% of patients carried germline MUTYH variants, predominantly monoallelic P/LP founder substitutions. These findings support inclusion of MUTYH in multigene germline testing for pediatric CNS tumors and warrant further studies to clarify its role as a low-penetrance susceptibility factor and potential modifier in neuro-oncogenesis.
Baldo et al. (Tue,) studied this question.