Germline JAK2 R564Q variants presenting as hereditary thrombocytosis: case report

Area of Science:

• Hematology
• Genetics
• Oncology

Background:

• Myeloproliferative neoplasms (MPNs) are often linked to somatic mutations in JAK2, CALR, and MPL.
• Germline variants, particularly in JAK2, can predispose individuals to MPN-like disorders, such as hereditary thrombocytosis (HT).
• The JAK2 R564Q variant is an activating germline mutation associated with hereditary MPN-like syndromes.

Purpose of the Study:

• To present three cases of hereditary thrombocytosis (HT) with the germline JAK2 R564Q variant.
• To highlight conflicting classifications of the JAK2 R564Q variant in clinical reports.
• To advocate for germline testing in specific MPN patient populations.

Main Methods:

• Case report analysis of three unrelated individuals with HT and the JAK2 R564Q variant.
• Review of clinical reports and variant classifications from different laboratories.
• Analysis of segregation data to assess variant pathogenicity.

Main Results:

• Three unrelated individuals with HT were identified with the germline JAK2 R564Q variant.
• Two patients received variant classifications of 'uncertain significance' in 2023.
• A third patient received a 'likely pathogenic' classification from a different laboratory, suggesting a need for re-evaluation.
• These cases provide segregation data supporting the pathogenicity of JAK2 R564Q.

Conclusions:

• The JAK2 R564Q variant's classification should be reconsidered as likely pathogenic.
• Germline testing for MPN predisposition should be considered for young patients, those with familial clustering, or idiopathic cases.
• Resolving conflicting variant classifications in databases like ClinVar is crucial for accurate diagnosis and patient management.