MLH1 is a component of the cellular DNA mismatch repair (MMR) machinery. The MLH1 V384D mutation has been associated with cancer risk in some tumor types. This variant encodes in a partially impaired protein with diminished interaction with PMS2 protein and reduced MMR activity in vitro. The MLH1 V384D variant has not been reported as a somatic mutation in glial brain tumors. This variant has an allele frequency of 4% in the East Asian population. Some studies have shown that patients carrying the MLH V384D variant have an increased risk of the development of microsatellite-instable as well as -stable colorectal cancer. MLH1 V384D variant has also been reported to be associated with primary resistance to EGFR-TKIs in patients with EGFR L858R-positive lung adenocarcinoma. Of note, this variant is reported as a benign germline variant in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/41632/). Clinical correlation is recommended.