Germline JAK2 R564Q variants presenting as hereditary thrombocytosis: case report

Myeloproliferative neoplasms (MPNs) are classically attributed to somatic variants in JAK2, CALR, and MPL, with epidemiologic studies demonstrating an increased risk for MPNs within first-degree relatives. Germline variants associated with MPN predisposition include rare variants of low population frequency/high penetrance alleles, often in JAK2, resulting in non-clonal MPN-like disorders, including hereditary thrombocytosis (HT). The first activating germline JAK2 variant encoding a residue other than V617F identified in association with a hereditary MPN-like syndrome was c.1691 G > A, p.Arg564Gln (R564Q), a gain-of-function missense variant. Here, we present the cases of three unrelated individuals with HT and the germline JAK2 R564Q variant, two of whom were tested in 2023, and received clinical reports classifying the variant as a variant of uncertain significance, and the third, tested more recently from a different laboratory, which classified the variant as likely pathogenic (LP). We propose that germline testing should be offered at minimum to MPN patients presenting at a young age, those with apparent familial clustering, and those with triple negative/idiopathic disease. These three cases provide additional segregation data that should sway consensus regarding the pathogenicity of this variant toward LP and resolve the conflicting classifications for this variant in ClinVar.