Germline mutations in the DNA repair gene () are established predisposing factors for colorectal polyposis, colorectal carcinoma, and various extracolonic malignancies. Nevertheless, the association between mutations and central nervous system (CNS) tumorigenesis remains poorly characterized. In this study, we reported the first identification of a novel c.467G > A (p.W156∗) variant in two patients with high-grade astrocytoma, , which was classified as pathogenic. Histopathological evaluation revealed tumor morphologies consistent with either diffuse glioma or giant cell glioblastoma. Comparative analysis with mismatch repair (MMR)-deficient tumors demonstrated that patients carrying mutations exhibited microsatellite stability, relatively low tumor mutation burden (TMB), and an immunosuppressive microenvironment, indicating difficulties in benefiting from immunotherapy. Fortunately, gain of Chromosome 7, in association with amplification of the gene, was detected, underscoring the possible application of targeted drugs. Integrating previous studies, we summarized germline mutations in 11 cases of high-grade neuroepithelial tumors (eight gliomas and three medulloblastomas). This cohort demonstrated a predilection for pediatric and young adult populations without significant gender predominance. Our findings suggested a potential association between germline mutations and CNS tumor susceptibility.