Print JAK2 and MPL Mutation Analysis in Myeloproliferative Neoplasms

JAK2 and MPL Mutation Analysis in Myeloproliferative Neoplasms



The Myeloproliferative Neoplasms (MPNs) are a category of uncommon overlapping blood diseases characterized by the production of one or more blood cells - chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), systemic masteocytosis, chronic eosinophilic leukemia and others.  A common finding in many of the MPNs is clonality.  A central pathogenic feature is the presence of a mutated version of the tyrosine kinase enzyme, such that it is abnormally constitutively activated.  The paradigm for use of this information to revolutionalize patient management is CML.  A unique chromosomal change (the Philadelphia chromosome) and an accompanying unique gene arrangement (BCR-ABL) resulting in a continuously activated tyrosine kinase enzyme were identified and led to discovery of a targeted tyrosine kinase inhibitor drug treatment (imatinib) that produces long-lasting remissions.

Diagnosis and monitoring of patient with Philadelphia chromosome negative MPNs have been challenging because many of the laboratory and clinical features of the classic forms of these diseases (PV, ET and PMF) can be mimicked by other conditions such as reactive or secondary erythrocytosis, thrombocytosis or myeloid fibrosis.  In addition, these entities can be difficult to distinguish on morphological bone marrow exam and diagnosis can be complicated by changing disease patterns.  For an example, PV and ET can evolve into PMF or undergo leukemic transformations. 

World Health Organization criteria were published as a benchmark for diagnosis in 2001.  These have been challenging to use because they involve complex diagnostic algorithms, rely on morphological assessment of uncertain consistency, and require tests such as endogenous erthyroid colony formation that are not well standardized or widely available.

In March and April of 2005, four separate groups using different modes of discovery and different measurement techniques reported the presence of a novel somatic point mutation in the conserved autoinhibitory pseudokinase domain of the gene coding for Janus Kinase 2 (JAK2) protein in patients with MPNs.  The mutation was noted to cause a valine-to-phenylalanine substitution at amino acid position 617 (JAK2V617F).  Loss of JAK2 autoinhibition caused by JAK2V617F results in constitutive activation of the kinase and in recruitment and phosphorylation of substrate molecules including signal transducers and activators of transcript (STAT) proteins (so-called JAK-Stat signaling).  The result is cell proliferation independent of normal growth factor control.  These findings were subsequently confirmed and additional mutations affecting the JAK2 gene--mutation in exon 14-- or involved in complementary pathways such as the thrombopoietin receptor pathway--mutations in MPL exon--were identified.  In addition, unique cases of JAK2 mutations were reported in subset of patients with Down syndrome acute lymphoblastic leukemia (ALL).

While these mutations were of importance in better understanding of the biology of the MPNs, they were also of immediate interest as laboratory tools to aid in diagnosis and management of disease.  To that end, at least four potential intended uses for mutation testing have been considered, including:

  1. Diagnosis of patients with clinical, laboratory or pathological findings suggesting MPNs particularly PV, ET or PMF;
  2. Evaluation of patients with Down syndrome ALL;
  3. Phenotyping of disease subtypes in patients with MPNs to establish disease prognosis;
  4. Identification, selection and monitoring of treatment.

More than a dozen commercial laboratories offer a wide variety of diagnostic procedures for JAK2 gene mutation testing and MPL testing.  These tests are available as laboratory developed procedures under the Federal Drug and Administration enforcement discretion policy for laboratory developed tests.  Variable analytical and clinical performance has been reported, suggesting that the nucleic acid amplification methodologies are more sensitive than mutation sequence analysis.  It appears that there can be considerable inter-assay and inter-laboratory variability in the generation of testing results.



JAK2 tyrosine kinase and MPL mutation testing may be considered medically necessary in the diagnosis of patients presenting with clinical, laboratory or pathological findings suggesting classic forms of MPNs particularly PV, ET or PMF.

JAK2 tyrosine kinase and MPL mutation testing is considered investigational in all other circumstances including, but not limited to the following: 

  • Diagnosis of nonclassic forms of MPNs
  • Molecular phenotyping of patients with MPNs
  • Monitoring, management, or selecting treatment in patients with MPNs
  • Diagnosis or selection of treatment in patients with Down syndrome and acute lymphoblastic leukemia





Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member’s specific benefit plan language.



04/16/2010:  New policy added.

04/20/2011: Policy reviewed; no changes.

02/24/2012: Policy title changed from "Tyrosine Kinase Mutations in Myeloproliferative Neoplasms" to "JAK2 and MPL Mutation Analysis in Myeloproliferative Neoplasms" because MPL is not a tyrosine kinase. Policy statement unchanged. Added 81270, 81402, and 81403 to the Code Reference section.

04/16/2013: Policy statement reorganized for clarity purposes; intent unchanged.

03/13/2014: Policy reviewed; no changes. Removed deleted CPT codes 83890 - 83906 and 83912 from the Code Reference section.

12/31/2014: Code Reference section updated to revise the description of the following CPT codes: 81402 and 81403.



Blue Cross Blue Shield Association Policy # 2.04.60



This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes

Code Number



81270JAK2 (Janus kinase 2) (eg, myeloproliferative disorder) gene analysis, p.Val617Phe (V617F) variant 
81402Molecular pathology procedure, Level 3 (eg, > 10 SNPs, 2-10 methylated variants, or 2-10 somatic variants [typically using non-sequencing target variant analysis], immunoglobulin and T-cell receptor gene rearrangements, duplication/deletion variants 1 exon), loss of heterozygosity [LOH], uniparental disomy [UPD])  (Revised 01-01-2015)
81403Molecular pathology procedure, Level 4 (eg, analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons)  (Revised 01-01-2015)

ICD-9 Procedure



ICD-9 Diagnosis


Polycythemia vera


Essential thrombocythemia


Myelofibrosis with myeloid metaplasia