SETD2 protein is a histone H3 lysine 36 trimethylating (H3K36Me3) enzyme affecting chromatin accessibility and DNA methylation. In addition, SETD2 plays an important role in DNA damage repair through promoting homologous recombination, mismatch repair, and activation of p53-mediated checkpoints. SETD2 gene is mutated in 10–15% of ccRCC tumors. Mutational analyses indicate that SETD2 mutations tended to be subclonal, and are thought to be associated with advanced tumor stage at presentation and a higher rate of metastatic disease, as well as decreased survival. Furthermore, SETD2 mutations occur more frequently when PBRM1 is mutated, suggesting that these mutations could be cooperating with each other.