JAK2 V617F - GET-Evidence


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JAK2 V617F

(JAK2 Val617Phe)

Short summary

This well known variant is associated with myeloproliferative diseases: it is used as a diagnostic, providing supporting evidence in individuals who already have symptoms. It is seen as an acquired (not inherited) mutation, one of an accumulation of changes that leads to the development of these cancer-like diseases. It is possible to see this variant in whole genome data or genotyping from blood-derived DNA — but it is unclear how to view the presence of the variant in individuals who don’t have symptoms of the disease. Data from Nielsen et al. suggests that such carriers are at much higher risk of developing myeloproliferative disease or other blood cancer (with roughly 50% of still-living individuals developing these diseases by around 10 years after initial samples — but these numbers are extremely uncertain).

Variant evidence
Computational 1

Polyphen 2 predicts damaging, gene & variant known to be associated in individuals already diagnosed

See Baxter EJ et al. 2005 (15781101).

Functional 4

active in absence of erythropoietin signalling, loss-of-heterozygosity observed clinically is consistent with suppression of this activity gain by wildtype JAK2, cell lines with JAK2-V617F became able to grow independently of growth factors, mice with JAK2-V617F bone marrow transplants had significantly high volume of red blood cells in their blood.

See James C et al. 2005 (15793561).

Case/Control 5

p=7*10^-22 for myeloproliferative disease and p=2*10^-32 for hematological cancer

See Nielsen C et al. 2011 (21160067).


No familial data; cases to date appear to be acquired mutations (rather than inherited)

Clinical importance
Severity 4

Polycythemia vera, Essential thrombocytosis, Myelofibrosis

Treatability 4

Polycythemia vera and essential thrombocytosis are fairly treatable

Penetrance 4

Chance for subsequent development of myeloproliferative disorder and/or blood cancer unclear, may be 20%-50% range.

See Nielsen C et al. 2011 (21160067).



High clinical importance, pathogenic

(The "high clinical importance, " qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary

This variant was discovered in the context of myeloproliferative diseases, and is a standard component in the diagnosis of these diseases — patients which have symptoms of the disease are tested for the presence of this variant, which is viewed as confirmatory evidence. How to react when an assumed-healthy individual presents with the variant is largely unknown. The variant has to date been reported as an acquired (not inherited) pre-cancerous mutation in blood stem cells. As genotyping / exome sequencing / whole genome sequencing are often performed using blood-derived DNA, this is sampling the appropriate tissue for detecting the acquired mutation.

The most relavent study is probably Nielsen et al. (data from the Copenhagen City Heart Study), which found 18 individuals with the variant. They report using the testing method of Baxter et al., implying a low sensitivity examination of Sanger sequencing — this is very similar to the sensitivity we would expect from whole genome sequencing. Other reports (Xu et al., Lauw et al.) use much more sensitive allele-specific PCR testing to detect very low levels of the variant (0.25% and 0.1% respectively); levels this low would typically be rejected as sequencing errors when analyzing genotyping or sequencing data.

Nielsen et al. report significantly increased rates of myeloproliferative and other hematologic cancers were later reported for the individuals found to carry the variant: of 15 individuals without diagnosis of hematologic cancer at the time of blood sample, 4 developed some sort of hematologic cancer in the 18 years that followed, 2 of which were myeloproliferative disorders. (Note that these are all retrospective analyses of records; patients were not specifically monitored for this disease, and so others may have gone undiagnosed.) According to Figure 1, individuals still living after 5-10 years had around a 50% chance of some type hematologic cancer (note that these are extremely small numbers, however, and so a lot of uncertainty exists). Also note that polycythemia vera, essential thrombocytosis, and primary myelofibrosis are described “myeloproliferative cancer” in this study — these myeloproliferative diseases cause excess amounts of blood cells but are not typically called “cancer”.

Allele frequency

  • T @ chr9:5073770: 0.0% (3/10756) in EVS
  • Frequency shown in summary reports: 0.0% (3/10756)


Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR; Cancer Genome Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005 Mar 19-25;365(9464):1054-61. Erratum in: Lancet. 2005 Jul 9-15;366(9480):122. PubMed PMID: 15781101.

This variant was found in a large number of cases of myeloproliferative disorders: 71 of 73 patients with polycythaemia vera (97%), 29 of 51 with essential thombocythaemia (57%), and 8 of 16 with idiopathic myelofibrosis (50%). The mutation was detected in granulocytes, which are descended from a myeloid precursor. In 30 cases T-cells (instead descending from a lymphoid precursor) were tested and found not to carry the mutation, indicating this variant is always, or almost always, an acquired mutation and not inherited.

The mutation was not detected in 90 control samples (from a population with type I diabetes).

James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C, Garçon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005 Apr 28;434(7037):1144-8. PubMed PMID: 15793561.

Functional data in this study confirms the effect of this variant as having an activating effect on JAK2. The authors found that the JAK2-V617F protein was constitutively active in the absence of erythropoietin & erythropoietin receptor signalling while wild type was not, and even more active (and more active than the wildtype control) when Epo and EpoR were both present.

Because many patients also have a loss of heterozygosity in the JAK2 gene leading to homozygosity for JAK2-V617F, the authors also tested whether the wildtype JAK2 has an effect on JAK2-V617F’s activation. They found cotransfection with wild type JAK2 abolished JAK2-V617F’s increased activity.

Expressing the JAK2-V617F mutant in cells lines dependent on growth factors created cell lines that could grow independent of growth factors, while control cells (with wildtype JAK2 or no treatment) died within 36 hours. With JAK2-V617F, the new cell line could be maintained for several weeks without growth factors and had a growth rate comparable to control cells on growth factors.

To test the in vivo effect of JAK2-V617F, mice were transplanted with bone marrow cells containing either JAK2-V617F, wild type JAK2 (control), or an empty vector (control). The mice receiving the JAK2-V617F bone marrow had significantly increased portion of their blood consisting of red blood cells (60% by volume), while untreated and control mice had levels around 40-42%.

Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D'Andrea A, Fröhling S, Döhner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005 Apr;7(4):387-97. PubMed PMID: 15837627.

A variety of patients with myeloproliferative disorders were profiled, sorted by self-reported disease status. Out of 164 genotyped individual with polycythaemia vera 84% carried the variant — 26 did not have the mutation, 80 were heterozygous, and 41 homozygous (presumably due to loss of heterozygosity). Of 115 genotyped with essential thrombocythemia 32% carried the variant — 78 did not have the mutation, 34 were heterozygous, and 3 were homozygous. Of 46 with myeloid metaplasia with myelofibrosis 35% carried the variant — 30 did not have the mutation, 12 were heterozygous, and 4 were homozygous.

In addition, the study genotyped this position in 269 samples from a panel collected by the International HapMap Consortium, all were homozygous for the wild-type variant. However, many of these were trios, only 420 of the 540 chromosomes tested were independent (120 from Utah NW European, 120 from Nigeria Yoruban, 90 from Han Chinese, 90 from Japanese) — assuming the one failed test accounts for a single individual, this represents 418 unrelated chromosomes found to carry the wild-type variant (equivalent to 209 individuals).

Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005 Apr 28;352(17):1779-90. PubMed PMID: 15858187.

Of 128 patients with polycythemia vera 65% carried the variant — 48 were heterozygous for the variant, and 35 were homozygous for it. Of 93 patients with essential thrombopenia 23% carried the variant — 18 were heterozygous for it, 3 homozygous. Of 23 patients with idiopathic myelofibrosis 57% carried the variant — 8 were heterozygous for it, 3 homozygous.

Of 71 healthy controls, none had this variant. This was also true for 9 patients with chronic myelogenous leukemia and 11 with secondary erythrocytosis.

Notably, the numbers reported here differ dramatically from those reported by Baxter et al. (71/2 carrier/non-carrier in Baxter et al. vs. 83/45 here, for PV cases). This may reflect differences in methods for disease diagnosis.

Steensma DP, Dewald GW, Lasho TL, Powell HL, McClure RF, Levine RL, Gilliland DG, Tefferi A. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and myelodysplastic syndromes. Blood. 2005 Aug 15;106(4):1207-9. Epub 2005 Apr 28. PubMed PMID: 15860661; PubMed Central PMCID: PMC1895198.


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PubMed PMID: 15920007

This study also studies the incidence of the JAK2 V617F variant in patients with myeloproliferative disorders. Of 160 healthy controls tested, none carried the variant. The variant was also not seen in 28 cases of systemic mastocytosis, 35 cases of chronic or acute myeloid leukemia, and 4 cases of secondary erythrocytosis.

Of 72 polycythemia vera patients, 58 (81%) had this variant and 24 of these were homozygous. Of 59 essential thrombopenia patients, 24 (41%) had the variant and 4 of these were homozygous. Of 35 idiopathic myelofibrosis patients, 15 (43%) had this variant and 10 were homozygous.

The authors also explored presence of this variant in rarer myeloproliferative disorder subtypes. Of 134 patients with idiopathic hypereosinophilic syndrome, 2 (1.5%) had the variant, both were homozygous. In addition, they examined related diseases which have some overlap: atypical chronic myeloid leukemia (aCML) and chronic myelomonocytic leukemia (CMML) (both combined in a group as “CML-like MPDs”) and atypical, unclassified cases of myeloproliferative disorder (unclassified MPD). Of 99 cases of CML-like MPDs, 17 (17%) carried the variant, 8 of which were homozygous. Of 53 cases of unclassified MPD, 13 (25%) carried the variant, 7 of which were homozygous.

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PubMed PMID: 16675710


Xu X, Zhang Q, Luo J, Xing S, Li Q, Krantz SB, Fu X, Zhao ZJ. JAK2(V617F): Prevalence in a large Chinese hospital population. Blood. 2007 Jan 1;109(1):339-42. Epub 2006 Aug 31. PubMed PMID: 16946305; PubMed Central PMCID: PMC1785080.

Using an allele-specific PCR method as a highly sensitive assay for presence of this variant (as low as 0.25% — similar to what was done by Lauw et al.), these authors report 37 samples from a total of 3935 (~1%) test positive for the mutation. Only one of these had blood test results consistent with polycythemia vera. On average the samples did have higher white blood cell and platelet counts; the authors conclude that the mutation may be a prelude to myeloproliferative disease but does not by itself diagnose it.

Tefferi A, Levine RL, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Finke CM, Mullally A, Li CY, Pardanani A, Gilliland DG. Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia. 2009 May;23(5):900-4. doi: 10.1038/leu.2009.37. Epub 2009 Mar 5. PubMed PMID: 19262599.


Thiele J, Kvasnicka HM. The 2008 WHO diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Curr Hematol Malig Rep. 2009 Jan;4(1):33-40. PubMed PMID: 20425436.


Nielsen C, Birgens HS, Nordestgaard BG, Kjaer L, Bojesen SE. The JAK2 V617F somatic mutation, mortality and cancer risk in the general population. Haematologica. 2011 Mar;96(3):450-3. Epub 2010 Dec 15. PubMed PMID: 21160067; PubMed Central PMCID: PMC3046277.

Of 10,507 participants in the Copenhagen City Heart Study, 18 were found to have this variant. (The authors describe using the assay technique described by Baxter et al., which implies only an examination of sequencing traces — much less sensitive than some other detection techniques used e.g. by Lauw et al.) For overall survival of these individuals in the 17.6 years of follow-up, all 18 of these mutation carriers died. For comparison, an age-matched subset of 540 had only 348 die during this interval (64%) — this different was highly significance (p=0.00003).

Of these 18, 11 had no cancer at the time of blood sampling. 7 of these (63%) later developed some sort of cancer in the subsequent time period, compared to 129 out of 473 in the age-matched population (27%) — p=0.0001 for a difference.

Of the 18, 15 were known to have no myeloproliferative or other hemotologic cancer at the time of blood sampling. Two of these went on to develop myeloproliferative cancer (p=7*10^-22) and, in total, four went on to develop some type of hemotologic cancer (including the two with MPD), a significance of p=2*10^-32.

The authors conclude, “These results document that, in some cases, presence of the mutation precedes the clinical diagnosis of myeloproliferative cancer.” The authors also note that it is possible others of the 18 individuals had myeloproliferative disorders that had been undiagnosed or misdiagnosed, as they were not being studied with the specific intent of collecting data regarding myeloproliferative cancer.

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PubMed PMID: 21484303

Because venous thromboembolism can be the first symptom presenting when detecting myeloproliferative disorders (myeloproliferative neoplasms = MPN in this paper), these authors were curious if there was a higher rate of the JAK2 V617F variant (associated with MPN development) and MPN symptoms in patients with deep vein thrombosis. They screened 178 patients and 198 controls (without history of venuous thromboembolism) and found four patients and one control positive for this variant (individuals tested as positive if they had 0.1% of the V617E allele in DNA from whole blood).

None of these five had features of MPN, nor did they have these features upon later reassessment (47-85 months, median 68.5 months = 5 years 8.5 months). On reassessment the mutation was still detected in 3 of the 5.


Other external references

  • rs77375493
  • Score: 0.997 (probably damaging)
    Web search results (65200 hits -- see all)
  • A Unique Activating Mutation in JAK2 (V617F) Is at the Origin ...
    A Unique Activating Mutation in JAK2 (V617F) Is at the Origin of Polycythemia Vera and Allows a New Classification of Myeloproliferative Diseases ...
  • JAK2, the JAK2 V617F mutant and cytokine receptors.
    In JAK2-deficient cells, we showed that JAK2 V617F can transmit signals from ligand-activated TpoR or EpoR. ... A synergy between JAK2 V617F and insulin-like growth factor 1 ...
  • JAK2 Assay, Cincinnati Children's Hospital Medical Center
    The Division of Human Genetics at Cincinnati Children's offers JAK2 genetics testing. ... A specific mutation in the JAK2 gene, known as V617F, has been found to be present in a ...
  • JAK2 V617F Mutation in Patients With Catastrophic ...
    Abstract and Introduction: Study results highlight the diagnostic usefulness of JAK2 V617F testing in this setting and underscore the clinical significance of a ...
  • Clinical relevance of JAK2 (V617F) mutant allele burden
    Homozygous JAK2 (V617F) erythroid colonies are present in most patients with PV, but ... Schematic representation of JAK2 (V617F) allele burden (middle panel) ...
    JAK2 MutaScreen™ assays allow qualitative and semi-quantitative detection of the JAK2 V617F mutation from ... Sensitive and highly specific detection of the JAK2 V617F mutation ...
  • JAK2 V617F and Exons 12, 13 Mutation Analysis
    The JAK2 tyrosine kinase (V617F) was detected in most patients (greater than 80 percent) ... This assays detects the JAK2 V617F and exon 12 mutations, which helps ...
  • Blood -- The myeloproliferative disorder associated JAK2 ...
    The somatic JAK2 valine-to-phenylalanine (V617F) mutation has been ... The somatic valine-to-phenylalanine (V617F) mutation in JAK2 has been associated with a ...
  • JAK2 V617F Mutation Detection
    The JAK2 V617F somatic mutation is found in nucleated myeloid cells and erythrocytic ... The presence of JAK2 V617F is also useful in the diagnosis of ET or ...
  • Characterization of JAK2 V617F Allele Burden in Advanced ...
    Barosi G, Bergamaschi G, Marchetti M, et al. JAK2 V617F mutational status. predicts progression to large splenomegaly and leukemic transformation in ...
    library.corporate-ir.net/.../ASH 2008 - Poster 2802.pdf

Other in silico analyses

  • NBLOSUM100 score = 3
  • GET-Evidence autoscore = 4

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