Acquired mutations (e.g., BCOR/NF1) in the proband suggest a 'two-hit' model for leukemogenesis.<h4>Conclusion</h4>This study identifies VHL as the principal predisposing mutation in a familial hematologic malignancy pedigree presenting with heterogeneous phenotypes, where ASXL3/CCR7 variants may serve as phenotypic modifiers. Here, NF1 is linked to hematologic disorder.