Clinical UM Guideline


Subject: Janus Kinase 2 (JAK2)V617F Gene Mutation Assay
Guideline #: CG-GENE-01 Publish Date:    12/27/2017
Status: New Last Review Date:    11/02/2017


This document addresses testing for the Janus Kinase 2 gene mutation.

The myeloproliferative disorders (MPD) also referred to as myeloproliferative neoplasms (MPN) are a large group of relatively rare pathogenetically related diseases arising in the bone marrow and characterized by the proliferation of one or more myeloid cell lines in the bone marrow resulting in increased numbers of relatively mature neoplastic cells in the peripheral blood. A point mutation (V617F) in the Janus Kinase 2 gene has been identified and found to be expressed in some individuals with one of three myeloproliferative diseases: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF).

The Janus Kinase 2 (JAK2) mutation assay has been developed to aid in the diagnosis of myeloproliferative disorders. A commercially available JAK2V617F mutation genetic test uses genomic DNA isolated from an individual’s blood. Polymerase chain reaction (PCR) assay technologies are used to analyze the specimen for the presence of the JAK2V617F gene mutation.

Clinical Indications

Medically Necessary:

Testing for the Janus Kinase 2 (JAK2; JAK2V617F) gene mutation is considered medically necessary for the initial diagnostic assessment of adults presenting with clinical, laboratory, or pathological findings suggesting classic forms of polycythemia vera (PV).

Testing for the Janus Kinase 2 (JAK2; JAK2V617F) gene mutation is considered medically necessary for the initial diagnostic assessment of BCR-ABL negative adults presenting with clinical, laboratory, or pathological findings suggesting classic forms of essential thrombocythemia (ET) or primary myelofibrosis (PMF).

Not Medically Necessary:

Testing for the Janus Kinase 2 (JAK2; JAK2V617F) gene mutation is considered not medically necessary for any other indication including but not limited to:


The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.




JAK2 (Janus kinase 2) (eg, myeloproliferative disorder) gene analysis, p.Val617Phe (V617F) variant


Molecular 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)  [when specified as the following]:

  • JAK2 (Janus kinase 2) (eg, myeloproliferative disorder), exon 12 sequence and exon 13 sequence, if performed

ICD-10 Diagnosis



Polycythemia vera


Myelodysplastic syndromes


Chronic myeloproliferative disease [primary myelofibrosis]


Essential (hemorrhagic) thrombocythemia



Discussion/General Information

MPD/MPN are a group of clonal malignancies characterized by dysregulation of a single hematopoietic stem cell, abnormal proliferation of one or more mature blood-cell types in the bone marrow with associated increases in peripheral blood parameters, and varying propensity to progress to bone marrow failure or acute myeloid leukemia (AML) (Spivak, 2003). Classification of the chronic myeloid processes is based primarily on the presence or absence of the Philadelphia (Ph) chromosome, (BCR-ABL translocation) and secondarily on the morphologic picture of the bone marrow in conjunction with the clinical manifestation. ET, PV and PMF constitute the classical group of BCR-ABL–negative chronic myeloproliferative disorders. These disorders share a common stem cell derived clonal heritage and their diversity is attributed to different mutations affecting tyrosine kinases or related molecules resulting in different configurations of abnormal signal transduction (Tefferi, 2007).

Although there are a number of shared clinical features across the conditions, each of the three BCR-ABL–negative MPD/MPN is considered a distinct clinical entity. ET is characterized by elevation in platelet count and megakaryocyte proliferation in the bone marrow. PV is distinguished by an increase in red blood cell (RBC) production, with resulting increases in RBC mass and hemoglobin and hematocrit levels. Frequently, platelet and white blood cell (WBC) count are also elevated. PMF is characterized by anemia, progressive splenomegaly and bone marrow fibrosis, and multi-organ extramedullary hematopoiesis. Most of these features, however, are not diagnostically specific, and secondary causes of erythrocytosis, thrombocytosis and bone marrow fibrosis must be excluded.

According to the World Health Organization (WHO) classification system for hematopoietic tumors, MPNs include chronic myelogenous leukemia (BCR-ABL1 positive [CML]), PV, PMF and ET. However, CML is unique in that it is the only one of these conditions that is positive for the BCR-ABL1 translocation. The others, PV, MF and ET are considered part of the operational sub-category of BCR-ABL1 negative conditions (Tefferi, 2012).

The Janus Kinase 2 V617F (JAK2V617F) point mutation is an acquired hematopoietic stem cell mutation where phenylalanine is substituted for valine at amino acid position 617 that results in unregulated JAK2 tyrosine kinase activity and JAK2 STAT signaling. Prior to the discovery of the JAK2V617F sequence variant, diagnosis for MPD/MPN was based on consensus criteria that relied primarily on measured variables, such as red cell mass, hematocrit, platelet count, and serum erythropoietin level, or on subjective techniques, such as bone marrow histology assessment. Use of arbitrary threshold levels increased concern that early-phase disease could be missed.

Tefferi (2005) and James (2006) found that it is possible that the JAK2V617F mutation is responsible for some portions of but not the complete phenotype in MPD/MPN. In 2007, Tefferi concluded that JAK2V617F is myeloid neoplasm-specific and its presence excludes secondary polycythemia, thrombocytosis, or bone marrow fibrosis from other causes. Furthermore, a JAK2V617F or a JAK2 exon 12 mutation is present in virtually all individuals with PV, whereas JAK2V617F also occurs in approximately half of those with ET or PMF. Therefore, JAK2V617F mutation is diagnostic for PV and complementary to histology for the diagnosis of ET and PMF and the combination of molecular testing. Histologic review should also facilitate diagnosis of ET associated with borderline thrombocytosis.

Further studies demonstrated that combination of JAK2V617F PCR testing and increased hematocrit is diagnostic for PV (sensitivity 95%, specificity 100%) (Michiels, 2007). Since the exclusion of PV is mandatory for the diagnosis of ET within the context of MPD/MPN, use of the test may facilitate the diagnosis of JAK2V617F –negative ET as well (Spivak, 2008). Additional information can be obtained from the degree of positivity of granulocytes. Homozygosity for JAK2V617, reflecting loss of heterozygosity as a result of mitotic recombination, is relatively specific to PV; the variant occurs in a homozygous state in 25% to 30% of those with PV but only in 2% to 4% of those with ET (Levinel, 2005; Vannucchi, 2007).

Research has also investigated whether the presence of the JAK2V617F sequence variant and mutational load in ET and PMF is associated with disease severity and with prognostic or therapeutic implications. There is insufficient knowledge to allow risk-stratification of individuals with ET and PMF based on qualitative or quantitative results of JAK2 variant testing. Furthermore, variant status designation is dependent on assay sensitivity and the issue is further confounded by the occurrence of marked variation in variant allele burden within this group.

The JAK2V617F sequence variant has lower penetrance among children with myeloproliferative disorders and cannot be used for diagnostic purposes in this age group. Currently available information does not warrant testing unaffected family members of individuals found to carry the JAK2V617F sequence variant.

The 2008 WHO criteria for the diagnosis of MPD/MPN explicitly recognize the importance of JAK2V617F testing, along with one other major criterion (such as hematocrit or red cell mass) for the definitive diagnosis of PV. The American Society of Hematology has recommended that screening for the JAK2V617F sequence variant be performed when a diagnosis of a myeloproliferative disorder is considered. One utility of JAK2V617F testing is suspected PV. Although the presence of the allele is not sufficient by itself to establish the diagnosis of PV, it may obviate the need for other testing including red blood cell mass and bone marrow biopsy.

The 2008 WHO revised criteria for the diagnosis of PV do not require the detection of a JAK2V617F mutation since an occasional individual might not display a mutation in routine clinical samples. Similarly, the absence of JAK2V617F has little diagnostic value in ET or PMF since approximately half of those individuals are JAK2 negative. In addition, current JAK2 assay systems may yield both false positive and false negative test results.  These issues were taken into account in the revised 2008 WHO diagnostic criteria for MPDs.  MPD consistent bone marrow is still a required criterion for the diagnosis of ET, PMF and the rare individual with JAK2V617F mutation-negative PV.  In addition, the availability of the JAK2V617F marker resulted in a lowering of the platelet count threshold for ET from 600 to 450 x 109 (Tefferi, 2008).


Allele: Any of the possible forms in which a gene for a specific trait can occur. In almost all animal cells, two alleles for each gene are inherited, one from each parent. Paired alleles (one on each of two paired chromosomes) that are the same are called homozygous, and those that are different are called heterozygous. In heterozygous pairings, one allele is usually dominant, and the other recessive. Complex traits such as height and longevity are usually caused by the interactions of numerous pairs of alleles, while simple traits such as eye color may be caused by just one pair.

BCR-ABL: A tyrosine-kinase oncogene. The Abelson leukemia-virus protein (ABL) is fused with the breakpoint-cluster region (BCR) in the Philadelphia-chromosome translocation found in chronic myeloid leukemia.

Mutation: A permanent transmissible change in DNA sequence. It can be an insertion or deletion of genetic information, or an alteration in the original genetic information.

Myeloid: Pertaining to, derived from, or manifesting certain features of the bone marrow.

Neoplasm: An abnormal growth of tissue caused by the division of cells that have experienced some type of genetic transformation or mutation.

Polycythemia: A condition marked by an abnormally large number of red blood cells in the circulatory system.

Polymerase chain reaction (PCR): A laboratory technique that employs artificial synthesis in a cyclic manner to amplify a specific target DNA fragment from a pool of DNA.

Proliferation: Rapid and repeated production of new parts (as in a mass of cells by a rapid succession of cell divisions).

Thrombocythemia: An increase above normal in the concentration of the blood platelets.

Tyrosine kinase: An enzyme involved in communication within cells, or signaling pathways. A mutation that causes certain tyrosine kinases to be constitutively active has been associated with several cancers.


Peer Reviewed Publications:

  1. Campbell P. Green, A. The myeloproliferative disorders. N Engl J Med 2006; 355(23):2452-2466.
  2. Campbell PJ, Scott LM, Buck G, Definition of subtypes of essential thrombocythemia and relation to polycythaemia vera based on JAK2V617F mutation status: a prospective study. Lancet. 2005; 366(9501):1945-1953.
  3. De Klein A, van Kessel AG, Grosveld G, et al. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukemia. Nature. 1982; 300(5894):765-767.
  4. James c, et al, Detection of JAK2V617F as first intention diagnostic test for erythrocytosis. Leukemia. 2006; 20(2):350-353.
  5. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005; 7(4):387-397.
  6. McLornan D, Percy M, McMullin M. JAK2V617F: a single mutation in the myeloproliferative group of disorders. Ulster Med J. 2006; 75(2):112-119.
  7. Michiels JJ, Bernema Z, Van Bockstaele D, et al. Current diagnostic criteria for the chronic myeloproliferative disorders (MPD) essential thrombocythemia (ET), polycythemia vera (PV) and chronic idiopathic myelofibrosis (CIMF). Pathol Biol. 2007; 55(2):92-104.
  8. Michiels JJ, De Raeve H, Hebeda K, et al. WHO bone marrow features and European clinical, molecular, and pathological (ECMP) criteria for the diagnosis of myeloproliferative disorders. Leuk Res. 2007; 31(8):1031-1038.
  9. Nelson ME, Steensma DP. JAK2V617F in myeloid disorders: what do we know now, and where are we headed? Leuk Lymphoma. 2006; 47(2):177-194. 
  10. Nussenzveig RH, Swierczek SI, Jelinek J, et al. Polycythemia vera is not initiated by JAK2V617F mutation. Exp Hematol. 2007; 35(1):32-38.
  11. Speletas M, Katodritou E, Daiou C, et al. Correlations of JAK2V617F mutation with clinical and laboratory findings in patients with myeloproliferative disorders. Leuk Res. 2007; 31(8):1053-1062.
  12. Spivak JL, Barosi G, Tognoni G, et al. Chronic myeloproliferative disorders. Hematology Am Soc Hematol Educ Program. 2003; 200-224.
  13. Tefferi A. Classification, diagnosis and management of myeloproliferative disorders in the JAK2V617F era. Hematology Am Soc Hematol Educ Program. 2006; 240-245.
  14. Tefferi A, Gilliland DG. Oncogenes in myeloproliferative disorders. Cell Cycle. 2007; 6(5):550-556.
  15. Tefferi A, Gilliland DG, Villeval JL, et al. The JAK2V617F tyrosine kinase mutation in myeloproliferative disorders: status report and immediate implications for disease classification and diagnosis. Mayo Clin Proc. 2005; 80(7):947-958.
  16. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Clinical profile of homozygous JAK2V617F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007; 110(3):840-846.
  17. Villeval JL, James C, Pisani DF, et al. New insights into the pathogenesis of JAK2V617F positive myeloproliferative disorders and consequences for the management of patients. Semin Thromb Hemost. 2006; 32(4):341-351.
  18. Walz C, Cross NC, Van Etten RA, Reiter A. Comparison of mutated ABL1 and JAK2 as oncogenes and drug targets in myeloproliferative disorders. Leukemia. 2008; 22(7):1320-1334.
  19. Wolanskyj AP, Lasho TL, Schwager SM, et al. JAK2 mutation in essential thrombocythemia: clinical associations and long-term prognostic relevance. Br J Haematol. 2005; 131(2):208-213.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. National Cancer Institute (NCI). Myeloproliferative Neoplasms. Available at: Accessed on September 21, 2017.
  2. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology™. © 2017 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website at: Accessed on September 21, 2017.
    • Myelodysplastic Syndromes. V1.2017. Revised August 18, 2016.
  3. Spivak J, Silver R. The revised World Health Organization diagnostic criteria for polycythemia vera, essential thrombocytosis, and primary myelofibrosis: an alternative proposal. Blood. 2008; 112(2):231-239.
  4. Tefferi A. Polycythemia vera and essential thrombocythemia: 2012 update on diagnosis, risk stratification, and management. Am J Hematol. 2012; 87(3):285-293.
  5. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2008; 22(1):14-22.

Essential Thrombocythemia
Idiopathic Myelofibrosis
JAK2 (Janus Kinase 2)
Myeloproliferative Diseases (MPD)
Myeloproliferative Neoplasms (MPN)
Polycythemia Vera

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Medical Policy & Technology Assessment Committee (MPTAC) review.



Hematology/Oncology Subcommittee review. Initial document development. Moved content of GENE.00004 to new clinical utilization management guideline document with the same title.