Nature and distribution of variants and clinical classification
After CHEK2 mutational analysis of 2,346 cases with suspicion of HC and discarding benign variants, we identified 51 different variants. Sixteen of which corresponded to variants expected to produce loss of function proteins or missense variants with conflicting interpretation in the literature (Table 1, Figure 2, pedigrees in Figure S1). The remaining 35 variants were clearly variants of unknown significance (VUS) (Table S1). The control group carried one conflicting interpretation missense variant and one VUS (Table 1 and Table S1).
To apply ACMG-AMP guidelines we split them based on the presence or absence of PVS1 (criterion for a predicted loss of function variant; Table 2).