SETD2 and cancer: A frequent mutational event in ccRCC is the (heterozygous) loss of the short arm of chromosome 3 (3p loss; [79], which contains many genes that are also individually mutated in ccRCC (leading to bi-allelic loss) such as VHL, PBRM1, BAP1, and SETD2. In ccRCC as well as in other cancer types, truncating mutations occur throughout SETD2, and given that the important SET and SRI domains are relatively close to the C-terminus of SETD2, all of these mutations are likely inactivating.