JAK2 p.R564 germ line variants associated with hereditary thrombocythemia and hematologic neoplasms

• Germline JAK2 R564Q/L cases may show MPN phenotype and present with or evolve into other hematologic neoplasms

• The symptomatic burden for individuals harboring germline JAK2 R564Q/L variants can be comparable to those with the canonical JAK2V617F hit.

The Janus kinase 2 (JAK2) V617F mutation activates the transcription pathway and has been well-characterized as a driver of myeloproliferative neoplasms (MPNs). Recently, there has been a heightened interest in understanding germline predisposition to hematological malignancies including MPN, including several reports of familial MPN. Here, we retrospectively analyzed medical records and data from genetic testing to describe twelve patients with germline variants at amino acid position 564 of JAK2. This includes three supportive cases adding to prior literature regarding the germline JAK2 R564Q association with hereditary thrombocythemia, as well as confirmation of JAK2 R564L as a germline variant associated with MPN. Importantly, the symptomatic burden for many of the individuals in this series is comparable to that of individuals with the canonical V617F mutation profile. In the JAK2 R564Q cases, we noted a pattern of familial aggregation, presence of congenital thrombocythemia and co-occurrence with hematological neoplasms. Identification of germline predisposition is essential to understanding the pathogenesis of disease, impact on families, and opportunities for preventive care. Continued research is essential to further characterize the penetrance of these conditions, and how best to monitor, treat and optimize management for these families.