Pathogenic mutations inMLH1,MSH2,PMS2, andMSH6compromise DNA mismatch repair mechanisms and in the heterozygous state result in Lynch syndrome, which is typified by a predisposition to endometrial, ovarian, colorectal, gastric, breast, hematologic, and soft tissue cancers. Rarely, germline pathogenic aberrations in these genes are associated with the development of primary central nervous system tumors. We present a report of an adult female with no prior cancer history who presented with a multicentric, infiltrative supratentorial glioma involving both the left anterior temporal horn and left precentral gyrus. Surgical treatment and neuropathological/molecular evaluation of these lesions revealed discordant isocitrate dehydrogenase (IDH) status and histologic grade at these spatially distinct disease sites. A frameshift alteration within theMLH1gene (p.R217fs*12, c.648delT) was identified in both lesions and subsequently identified in germline testing of a blood sample, consistent with Lynch syndrome. Despite distinct histopathologic features and divergent IDH status of the patient's tumors, the molecular findings suggest that both sites of intracranial neoplasia may have developed as a consequence of underlying monoallelic germline mismatch repair deficiency. This case illustrates the importance of characterizing the genetic profile of multicentric gliomas and highlights the oncogenic potential of germline mismatch repair gene pathogenic alterations within central nervous system gliomas.