Whereas in patients with KS many missense variants have a loss-of-function (LoF) effect (by impaired methyltransferase activity and/or loss of protein–protein interactions) [127] it can not be excluded that some missense variants in cancer may have a gain-of-function [126] or, in analogy to selected germline KMT2D missense variants [128] a dominant-negative effect [126]. The gene discussed is KMT2D; the disease is cancer.