Framework to Identify and Prioritize Candidate Inherited Myeloid Malignancy Germline Variants Leveraging the BEAT AML Cohort

Background: Familial predisposition to myeloid malignancies is more common than previously appreciated. 15-20% of acute leukemia patients have at least 1 additional first-degree relative with leukemia predisposition. Germline predisposition to myeloid neoplasms was incorporated in the WHO 2016 classification of myeloid neoplasms and acute leukemia. The clinical guidelines now include testing for inherited susceptibility as a critical element of patient diagnostics. Identification of germline predisposition syndrome can significantly impact treatment decisions, screening of potential sibling donors for allogeneic stem cell transplantation, and patient and family surveillance. Here we developed a framework to guide routine identification of potential pathogenic germline mutations for further characterization and aid in identification of individuals who are at high risk of developing leukemia so that these individual can be closely monitored for disease management and treatment interventions.