Fig. 4: Germline–CH interactions stratify the risk of hematologic malignancy.

a, HRs (center dot) and 95% CIs for myeloid or lymphoid malignancy among people with pathogenic variants in germline genes that predispose to both CH and hematologic malignancy (HM) stratified by the presence of any CH (including any CH-heme and mCA-auto). Differences between the risk of hematologic cancer across CH-positive and CH-negative germline carriers were calculated using Firth’s bias-reduced logistic regression limited to germline variant carriers. *P < 0.1, **P < 0.01, ***P < 0.001. The two-sided P value has no correction for multiple testing (see Supplementary Table 17 for exact P values). b, Predicted distribution of 25-year absolute risk of myeloid malignancies among UKBB individuals aged 50–74 years with CHEK2 (n = 3,012), ATM (n = 1,592) or no pathogenic germline variants (n = 269,050). Analyses in both a and b were performed using Cox’s regression adjusted for age at blood draw, first three genetic PCs and exome sequencing batch. c, Comparison of distribution of 25-year absolute risk of myeloid malignancy among people at the top percentiles of risk across people with CHEK2 (n = 30), ATM (n = 14) or no germline variant (n = 2,690). The center line represents the median, the box limits the upper and lower quartiles and the whiskers 1.5× the interquartile range (IQR).