The hereditary cancer predisposition disease Lynch syndrome (LS) is caused by disruption of theDNA mismatch repair (MMR) pathway, which leads to increased cellular mutation rates in thecell and thus makes patients prone to develop cancer. LS arises from mutations in one of the fourMMR genes, MLH1, MSH2, PMS2 and MSH6, and more than 1:300 in the general populationare estimated to be a carrier of a LS-linked mutation. However, the individual mutation effectsvary greatly and can be hard to interpret. As mutations may affect the protein stability, we usedthe computational tool, FoldX, to predict potential stability changes in all possible missensevariants of the MLH1 protein. We measured the cellular abundances of 69 missense MLH1variants associated with LS and found that stability correlates with measured abundance andfunction of the variants. Deeper analysis revealed that low MLH1 abundances are caused bydegradation through the ubiquitin-proteasome system (UPS) assisted by the molecular chaperoneHSP70 and co-chaperone HSP110 — key factors of the protein quality control (PQC)machinery. In the light of this, we contemplated how the PQC might discriminate pathogenicprotein variants from benign. UPS-mediated degradation depends on detection of degradationsignals – degrons – within the destabilized and unfolded protein structure. However, little isknown about the features of degrons within misfolded proteins (PQC degrons) as well as howthese are detected. Thus, in a separate study in yeast, we constructed a peptide library in a Ura3-GFP-based reporter system and screened for degron function, hoping to find general features thatdefine degron motifs. With this screen, we show that degron motifs preferentially display anincrease in hydrophobic residues and a reduction of negatively charged residues — features thatresemble the canonical HSP70 binding motif, RLLL. Accordingly, we found that the RLLL-motif itself functions as a degron, and we propose that many PQC degrons may be regions adeptat chaperone binding.