Our combined data demonstrating that SETD2 deficient ccRCC-derived cells are significantly sensitive, less migratory, and less capable of forming spheroids and that tumor formation of SETD2 mutant xenografts is abrogated, further underscore the biological relevance of this molecular connection between SETD2 and PI3Kβ. Here, SETD2 is linked to nonpapillary renal cell carcinoma.