Myeloid neoplasms, including acute myeloid leukemia, have been traditionally among the less investigated cancer types concerning germline predisposition. Indeed, myeloid neoplasms with germline predisposition are challenging to identify because often display similar clinical and morphological characteristics of sporadic cases and have similar age at diagnosis. However, a misidentification of familiarity in myeloid neoplasms have a critical impact on clinical management both for the carriers and their relatives. We performed a thorough genomic analysis using a large custom gene panel, the Myelo-Panel, targeted on cancer predisposing genes. In particular, we assessed both germline and somatic variants in 4 families, each with two siblings, who developed hematological neoplasms: 7 acute myeloid leukemia and 1 Philadelphia-positive chronic myeloid leukemia. In each family, we identified at least one novel potentially predisposing variant, affecting also genes not included in the current European LeukemiaNet guidelines for AML management. Moreover, we suggest reclassification of 2 germline variants as pathogenic: likely pathogenic p.S21Tfs*139 in CEPBA and VUS p.K392Afs*66 in DDX41. Our data underline how familiar predisposition to hematological neoplasms is currently underestimated and call for revision of clinical practices that should include thorough reconstruction of family history and genetic testing with gene panels targeted for cancer predisposing genes.