SETD2 encodes a H3K36 trimethylase and loss of function mutations (missense, nonsense and frameshift mutations) have been reported in approximately 10% of acute myeloid leukemia, and 10% of acute lymphoblastic leukemia, including acute early T cell precursor acute lymphoblastic leukemia. SETD2 mutations appear to be enriched among cases of acute leukemia with rearrangements of MLL. Coexistence of two mutations in SETD2 has been described and together with recurrent loss of function mutations suggest this gene is acts as a tumor suppressor. The presence of loss of function mutations in SETD2 has been associated with global loss of H3K36me3. In addition, the presence of SETD2 mutations may be associated with therapy resistance.

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.

This gene is a known cancer gene.

This gene is a known cancer gene.