Impact of Germline CHEK2 Pathogenic Variants on the Risk of Acute Myeloid Leukemia and Myelodysplastic Syndrome

Pathogenic (P) germline variants in CHEK2 are associated with a moderately increased risk of several solid tumors; however, their contribution to myeloid malignancies remains poorly defined.

We analyzed germline CHEK2 variants in 1,035 patients with acute myeloid leukemia (AML) and 283 with myelodysplastic syndromes (MDS). P and likely pathogenic (LP) variants were identified, and their frequency, type, and clinical context were evaluated, including family and personal cancer histories.

P/LP CHEK2 variants were found in 1.74% of patients with AML and 1.77% of MDS cases. Although founder variants such as c.1100delC and p.I157T were present, most were rare missense variants with a population allele frequency below 0.001. These variants were significantly enriched in AML and MDS, even after adjusting for ethnicity. Notably, 39% of patients with AML with P/LP CHEK2 variants had a history of solid tumors or hematologic malignancies. Family history of cancer was also frequent, with 21% reporting hematologic and 57% reporting solid tumors.

Our findings support an expanded role for germline CHEK2 variants in predisposing individuals to myeloid neoplasms, in addition to their association with solid tumor risk.

Given the emerging evidence linking CHEK2 to clonal hematopoiesis (CH), these results underscore the need for prospective studies to refine risk assessment, inform genetic counseling, and guide surveillance strategies. These results suggest that clinical guidelines may consider monitoring CH in CHEK2 carriers and weigh the risks and benefits when considering CHEK2 carriers as stem cell transplant donors.