Renal clear cell carcinoma (ccRCC) is characterized by frequent mutation in SETD2, which has recently been shown to regulate mismatch repair (MMR). We aim to investigate the association between MMR machinery genes and SETD2 mutation in ccRCC. We exploited the Genomics of Drug Sensitivity in Cancer (GDSC) database to identify selective inhibitors for SETD2 mutant ccRCC cells. We also exploited the Cancer Genome Atlas (TCGA) database to study the association between SETD2 status and MMR-related genes. In vitro studies were performed to validate the in silico findings. Reproduction of the GDSC database revealed four compounds with significant selectivity for SETD2 mutant ccRCC cells, amongst which two compounds targeted PI3Kβ. Phosphorylation of AKT at both S473 and T308 was decreased following PI3Kβ inhibitor treatment in SETD2 mutant ccRCC cells, whereas the basal pAKT level was not changed between mutant and wild-type SETD2. Both decreased MLH1 and increased AKT levels induced lower PMS2, indicating that MMR was mediated by SETD2 via both AKT and MLH1 in ccRCC. Analysis of the TCGA database further revealed high tendency of homozygous co-deletion of SETD2 and MLH1. In the absence of MLH1, suppression of pAKT by PI3Kβ inhibitor was mitigated and inhibition in cell proliferation, invasiveness, migratory ability and tumourigenesis was partially restored. Besides the reported H3K36-trimethylation pathway, we found that SETD2 mutation also mediated MMR via AKT-induced PMS2 decrease and co-loss of MLH1 loss in ccRCC.