While the majority of myelodysplasia and acute myeloid leukemia (MDS/AML) cases are sporadic, rare familial predisposition syndromes have been delineated and now represent a separate disease entity in the revised World Health Organization (WHO) classification of myeloid neoplasms [1]. Germline mutations in~ 14 disease genes have been uncovered thus far, with GATA2 representing one of the key transcriptional regulators commonly mutated in inherited MDS/AML [2]. Increasing evidence suggests that aberrations in GATA2 impair its transcription and promoter activation, leading to a loss-of-function, supporting a mechanism of GATA2 haploinsufficiency [3–5]. Reduced penetrance, the observation that family members carry an identical germline mutation yet display variable clinical manifestations, is common and poses a clinical challenge in the diagnosis and management of familial leukemia's, particularly when identifying “silent” mutation carriers for genetic screening and exclusion as potential stem cell transplant donors [6, 7]. Indeed, we have noted that reduced penetrance is a feature among certain GATA2-mutated MDS/AML families [8], especially those harboring missense germline mutations such as c. 1061C> T (p. Thr354Met)(Table S1) although the precise molecular explanation of such occurrence has not been investigated. Analysis of five MDS/AML families harboring p. Thr354Met GATA2 mutations displayed significant intraand interfamilial variations in disease latency, phenotype, and penetrance (Figure S1). These observations suggest that individuals require additional co-operating events for the development of overt malignancy within the context of a shared germline mutation. To investigate this hypothesis further, we examined an extensive five-generation pedigree [9](Fig. 1a) where two first-degree cousins (IV. 1 and IV. 6) developed high-risk MDS/AML with monosomy 7, while a third cousin (IV. 10) presented with recurrent minor