Although multiple predispositions to hematologic malignancies exist, evaluations for hereditary cancer syndromes (HCS) are underperformed by most hematologist/oncologists. Criteria for initiating HCS evaluation are poorly defined, and results of genetic testing for hereditary hematologic malignancies have not been systematically reported.

From April 2014 to August 2015, 67 patients were referred to the Hereditary Hematologic Malignancy Clinic (HHMC). Referral reasons included (1) bone marrow failure or myelodysplastic syndrome in patients ≤50 years, (2) evaluation for germline inheritance of identified RUNX1, GATA2, or CEBPA mutations on targeted next-generation sequencing panels, (3) strong personal and/or family history of malignancy. Cultured skin fibroblasts were utilized for germline DNA in all patients with hematologic malignancy.

Eight (12%) patients were clinically diagnosed with a HCS; 4 patients with RUNX1-related familial platelet disorder (FPD)/AML, and one patient each with dyskeratosis congenita, Fanconi anemia, germline DDX41, and Li-Fraumeni Syndrome (LFS). Two patients with concern for FPD/AML and LFS, respectively, had RUNX1 and TP53 variants of unknown significance. Additionally, four patients with prior HCS diagnosis (1 LFS, 3 FPD/AML) were referred for further evaluation and surveillance.

In this HHMC-referred hematologic malignancy cohort, HCS was confirmed in twelve patients (18%). HCS identification provides insight for improved and individualized treatment, and screening/surveillance opportunities for family members. The HHMC has facilitated HCS diagnosis, and advocates that with increased clinical awareness of hematologic malignancy predisposition syndromes, more patients who may benefit from evaluation can be identified. Mutation panels intended for prognostication may provide increased clinical suspicion for germline testing.