TPMT and Lynch syndrome: Our observation that single amino acid changes in MLH1 are sufficient to cause degradation is similar to results from multiple other proteins including recent deep mutational scans on PTEN and TPMT (Matreyek et al., 2018), our previous results on MSH2 in human cells (Nielsen et al., 2017), and earlier observations on Lynch syndrome MSH2 variants in yeast (Gammie et al., 2007; Arlow et al., 2013).