Model of germline genetic context in clonal evolution. Acquired somatic clonal mutations may be adaptive (improve hematopoiesis) or maladaptive (lead to transformation), depending on the underlying genetic MDS predisposition. In SBDS-mutant hematopoietic stem/progenitor cells, iso7q or del20q are common adaptive clonal aberrations, whereas TP53 somatic mutation is maladaptive. Fanconi anemia development of +3q is associated with progression to malignancy, whereas somatic reversion is not. In SAMD9/9L disorders, correction of the mutation by reversion or loss of mutant via truncation is adaptive, whereas development of monosomy is associated with MDS or AML. TERC-mutant HSPCs may undergo somatic reversion to regain 2 wild-type TERC alleles. GOF, gain of function; LOF, loss of function; HSPC, hematopoietic stem/progenitor cells; WT, wild type. Professional illustration by Patrick Lane, ScEYEnce Studios.