Impact of Germline DNA Repair Mutations on Clonal Hematopoiesis and Myeloid Neoplasm Development

Emerging evidence suggests that germline perturbations in DDR pathway contribute to CH, though mechanisms remain incompletely defined. Large scale genome-wide association studies (GWAS) have identified strong associations between ATM and CHEK2 variants and CH. Assessing prevalence and CH risk in individuals with germline TP53 variants presents unique challenges, as distinguishing between somatic and constitutional lesions is often complex and requires careful tissue evaluation. The link between germline BRCA1/2 and CH remains inconclusive, confounded by concurrent diagnosis of solid malignancy and prior exposure to chemoradiation therapy in studied patient populations. Although germline mutations in PPM1D and PARP1 are rare, a potential germline predisposition to CH cannot be excluded. The totality of current evidence suggests that germline DDR pathway mutations not only predispose to well-established solid malignancy syndromes but also to CH, which independently increases the risk of hematologic malignancies. Recognizing germline contributions to CH has broad implications for risk assessment, surveillance strategies, and development of preventive strategies in myeloid neoplasia.