MSH2 and Lynch syndrome: Large positive changes in ∆∆G may be indicative of a loss of protein stability, and a recent comprehensive study of MSH2 mutations in Lynch syndrome has shown a correlation between high ∆∆G values and loss of stability or reduced function.12 It should be noted however that not all variants adhered to this general rule, and it is possible that structural perturbations in one part of the protein, resulting in high ∆∆G values as calculated by FoldX, might be accommodated without causing loss of stability in other regions or domains.