Fig. 3

A Bayesian integration of cell-free in vitro MMR activity (CIMRA) assay values and in silico predictions of pathogenicity correctly classifies ~90% of missense variants. (a) Receiver operating characteristic (ROC) curve of a cross-validation between the two CIMRA training runs. (b) ROC curve of a two-component (CIMRA assay + in silico) analysis. (c) Distribution of probabilities of pathogenicity for 68 missense variants as estimated by in silico analysis only (top), CIMRA only (middle), or integrated two-component analysis (CIMRA plus the computational Prior-P; bottom). The gray, dotted, lines highlight probabilities of 0.05 and 0.95. #: Because the probabilities of pathogenicity estimated by the computational Prior-P are capped at 0.1 and 0.9, the bins <0.08 and >0.92 are empty. (d) Subcellular localization of wild-type (WT) and mutant MLH1 protein. NIH3T3 cells were transiently transfected with pYFP-MLH1 WT (shown in red, left panel) together with pCFP-MLH1 (WT or mutant; shown in green, middle panel). The localization of the fusion proteins were analyzed using confocal laser scanning microscopy. The corresponding outline of cells in Nomarski contrast are shown (right panel) where the yellow color indicates overlay of the two proteins. IARC International Agency for Research on Cancer.