JAK2 V617F - GET-Evidence

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JAK2 V617F

(JAK2 Val617Phe)

You are viewing an old version of this page that was saved on December 29, 2011 at 5:03pm by Madeleine Ball.

Short summary


Variant evidence
Computational -
Functional -
Case/Control -
Familial -
Clinical importance
Severity -
Treatability -
Penetrance -


Insufficiently evaluated pathogenic

(The "insufficiently evaluated" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary


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).

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.

Edited in this revision:

Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L, Score J, Seear R, Chase AJ, Grand FH, White H, Zoi C, Loukopoulos D, Terpos E, Vervessou EC, Schultheis B, Emig M, Ernst T, Lengfelder E, Hehlmann R, Hochhaus A, Oscier D, Silver RT, Reiter A, Cross NC. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood. 2005 Sep 15;106(6):2162-8. Epub 2005 May 26. 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.


Other external references

  • 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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