Fig. 7: Concordance between the case-control likelihood ratio method and functional predictors.

Concordance is shown separately for a BRCA1 and b BRCA2. The top panels for each gene represent case-control likelihood ratios (LRs) compared to variants predicted as benign (“BP4 criterion”, “predicted benign” or “functional”) or pathogenic (“PP3 criterion”, “predicted pathogenic” or “loss-of-function”) by in silico prediction methods (AlphaMissense, BayesDel, MutPred2, VEST4 and REVEL) or through high-throughput functional assays (Findlay et al., 2018, Huang et al., 2025, Sahu et al., 2025, Hu et al., 2024, Mesman et al., 2019). Yellow and green colors represent variants predicted as pathogenic or benign by functional predictors, respectively. For visualization purposes the x axis represents log10(LR) values. Box plots with individual data points display the median value, with whiskers extending to a maximum of 1.5 × interquartile range (IQR) beyond the box. The notch in the box approximates the 95% confidence interval (CI) for the median. Bottom panels for each gene represent sequence-pathogenicity heatmaps demonstrating the concordance between the case-control LR (ccLR) method and functional predictors. For the case-control LR (ccLR) evidence, red color gradient represents LR reaching suggested ACMG/AMP evidence in favor of pathogenicity with strength levels ranging from very strong (dark red) to supporting (yellow). The green color gradient represents LR reaching suggested ACMG/AMP evidence against pathogenicity with strength levels ranging from very strong (dark green) to supporting (light green). Variants with ccLR of “No evidence” are not plotted. For the functional predictors, yellow and green colors represent evidence in favor and against pathogenicity, respectively (expressed as “pathogenic supporting”). The total number of variants included in the concordance analyses is depicted in Supplementary Data 6.