Pathogenicity predictions of <i>MSH2</i> mutations.

<p>(A) Distributions of FoldX ΔΔG scores for MSH2 variants tested in this work with short (red), intermediate (yellow), and long (light green) half-life (t½), common variants found in ExAC (dark green), known non-pathogenic (blue) and pathogenic (purple) variants, and recently identified pathogenic variants (RIPV, magenta) [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006739#pgen.1006739.ref030" target="_blank">30</a>]. Dots indicate the mean ΔΔG score for each group, and the bars indicate the standard error of the mean. (B) Receiver operating characteristics (ROC) curves for the selected predictors of MSH2 variant pathogenicity: co-variation (red), FoldX ΔΔG (yellow), Rosetta ΔΔG (green), PROVEAN (cyan), SIFT (blue), and PolyPhen2 (purple). Accuracy is assessed on known pathogenic and non-pathogenic variants according to Houlleberghs <i>et al</i>., 2016. As the area under the curve (AUC) indicates, while all predictors show reasonable performance, ΔΔG and co-variation provide considerably higher accuracy. (C) The distribution of FoldX ΔΔG scores vs. the allele frequency of MSH2 mutations found in the Exome Aggregation Consortium (ExAC) database. Note that alleles that are found at a high frequency in the population, and are therefore unlikely to be pathogenic, appear stable (display low ΔΔG values). The three horizontal lines correspond to quartiles. For further information, refer to <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006739#pgen.1006739.s006" target="_blank">S6 Fig</a>.