About JAK2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
JAK2 c.1849G>T, p.(Val617Phe)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 6
Benign evidence criteria: 0
Pathogenic criteria applied · 6
PS3Strong
PS3 · strong
Well-established functional studies demonstrate JAK2 V617F is a gain-of-function mutation. James et al. (2005) showed that V617F induces constitutive STAT5 transcriptional activation in luciferase reporter assays, transforms Ba/F3 cells to cytokine-independent growth, and causes erythrocytosis in a mouse bone marrow transplant model. Haan et al. (2009) confirmed constitutive activation of STAT1/3/5, ERK1/2, and p38 pathways, with SOCS-mediated feedback regulation. Sanz et al. (2011) demonstrated altered catalytic activity via peptide microarray. McKenney et al. (2018) confirmed oncogenicity in a Jak2V617F-driven MPN mouse model. Multiple independent studies with diverse functional assays consistently support a gain-of-function pathogenic mechanism.
PS4Strong
PS4 · strong
JAK2 V617F is the hallmark mutation in myeloproliferative neoplasms, reported in >80% of polycythemia vera, ~50% of essential thrombocythemia, and ~50% of primary myelofibrosis cases. It is virtually absent from the general germline population — gnomAD v2.1 shows global AF of 0.034% (97/281,626 alleles) with 5 homozygotes, and v4.1 shows 0.029% (471/1,605,918 alleles) with 17 homozygotes, frequencies that almost certainly represent somatic clonal hematopoiesis rather than true germline variation. The extreme case enrichment meets the PS4 threshold at the strong level.
PM1Moderate
PM1 · moderate
The p.Val617Phe substitution is located in the JH2 pseudokinase domain (amino acids ~545-809), a well-established critical regulatory domain that mediates autoinhibition of JAK2 kinase activity. The JH2 domain is a recognized mutational hotspot for gain-of-function variants in myeloproliferative neoplasms, with multiple activating mutations described at this locus (e.g., K539L, R564Q, E695K). Position 617 is specifically identified as a residue whose alteration disrupts autoinhibitory interactions with the JH1 kinase domain activation loop.
PM2Supporting
PM2 · supporting
The variant is present at very low frequency in gnomAD population databases: global AF 0.034% in v2.1 and 0.029% in v4.1, both below the 0.1% threshold for PM2. The maximum subpopulation frequency is 0.075% (Ashkenazi Jewish, v4.1). The presence of homozygotes (5 in v2.1, 17 in v4.1) is noted but is consistent with somatic clonal hematopoiesis in aging individuals rather than true germline homozygosity.
PP3Supporting
PP3 · supporting
REVEL score of 0.881 is above the established deleterious threshold (≥0.75). Multiple in silico predictors support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.01). HCI Prior is not available for JAK2.
PP5Supporting
PP5 · supporting
ClinVar reports the variant as Pathogenic by 14 clinical laboratories and Likely pathogenic by 5 laboratories (ClinVar variation ID 14662). Multiple reputable clinical diagnostic laboratories have independently classified this variant as pathogenic, supporting a disease-causing role.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PS4 strong, PM1 moderate, PM2 supporting, PP3 supporting, PP5 supporting; combination = 2 strong + 1 moderate + 3 supporting, which maps to Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
471 / 1,605,918 alleles
gnomAD v4.1: 471 / 1,605,918 alleles. Recorded AF 0.00029329. Recorded homozygote count 17.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000344428; MAF= 0.03444%, 97/281626 alleles, homozygotes = 5) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000579934; MAF= 0.05799%, 6/10346 alleles, homozygotes = 0); grpmax FAF= 0.00030518.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0005979560774081322, 11/18396 alleles, homozygotes = 0).
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
20 reported laboratory submissions
14 Pathogenic · 5 Likely pathogenic · 1 pathogenic.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
42916 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV67569051, n = 42916 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 6 met · 4 not met · 9 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
JAK2 c.1849G>T (p.Val617Phe) is the canonical activating mutation in myeloproliferative neoplasms, identified in >80% of polycythemia vera cases and a substantial proportion of essential thrombocythemia and primary myelofibrosis cases.
Well-established functional studies across multiple independent laboratories demonstrate that V617F disrupts JH2 pseudokinase domain autoinhibition, resulting in constitutive JAK2 kinase activity, STAT-mediated transcriptional activation, cytokine-independent cell growth, and erythrocytosis in murine models.
The variant is located in the JH2 pseudokinase domain, a critical regulatory region and established mutational hotspot for gain-of-function variants in myeloproliferative neoplasms.
Population databases show the variant at very low frequency (gnomAD v2.1: 0.034%; v4.1: 0.029%), well below the 0.1% PM2 threshold. Observed homozygotes are consistent with somatic clonal hematopoiesis rather than germline events.
REVEL in silico prediction score of 0.881 supports a deleterious effect on protein function.
ClinVar reports the variant as Pathogenic by 14 clinical diagnostic laboratories and Likely pathogenic by 5, with variation ID 14662.
Two strong pathogenic criteria (PS3 + PS4) satisfy the '2 Strong' pathogenic combination rule under the generic ACMG/AMP 2015 framework. Additional moderate (PM1) and supporting criteria (PM2, PP3, PP5) provide further confirmatory evidence.
No criteria match.
Met · 6
PS3 StrongWell-established functional studies demonstrate JAK2 V617F is a gain-of-function mutation. James et al. (2005) showed that V617F induces constitutive STAT5 transcriptional activation in luciferase reporter assays, transforms Ba/F3 cells to cytokine-independent growth, and causes erythrocytosis in a mouse bone marrow transplant model. Haan et al. (2009) confirmed constitutive activation of STAT1/3/5, ERK1/2, and p38 pathways, with SOCS-mediated feedback regulation. Sanz et al. (2011) demonstrated altered catalytic activity via peptide microarray. McKenney et al. (2018) confirmed oncogenicity in a Jak2V617F-driven MPN mouse model. Multiple independent studies with diverse functional assays consistently support a gain-of-function pathogenic mechanism. Details ▾Hide ▴
Evidence considered
- Constitutive STAT5 activation in luciferase reporter assay (gamma-2A cells)
- Cytokine-independent growth transformation of Ba/F3 and FDCP-EpoR cells
- Erythrocytosis induction in murine bone marrow transplant model
- Constitutive phosphorylation of STAT1/3/5
- ERK1/2
- p38
- and AKT
- SOCS-mediated feedback regulation and ubiquitin-proteasome degradation
- Altered catalytic activity confirmed by peptide microarray
- Jak2V617F-driven MPN mouse model demonstrates oncogenicity
Sources
PS4 StrongJAK2 V617F is the hallmark mutation in myeloproliferative neoplasms, reported in >80% of polycythemia vera, ~50% of essential thrombocythemia, and ~50% of primary myelofibrosis cases. It is virtually absent from the general germline population — gnomAD v2.1 shows global AF of 0.034% (97/281,626 alleles) with 5 homozygotes, and v4.1 shows 0.029% (471/1,605,918 alleles) with 17 homozygotes, frequencies that almost certainly represent somatic clonal hematopoiesis rather than true germline variation. The extreme case enrichment meets the PS4 threshold at the strong level. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 global AF = 0.034% (97/281
- 626 alleles
- 5 homozygotes)
- gnomAD v4.1 global AF = 0.029% (471/1
- 605
- 918 alleles
- 17 homozygotes)
- Reported in >80% of polycythemia vera patients (James et al. 2005)
- ClinVar: Pathogenic by 14 clinical laboratories
- Likely pathogenic by 5
- COSMIC: 42
- 916 somatic occurrences
Still missing
- Formal case-control odds ratio not calculated — enrichment is well-established in the literature but quantitative OR/CI not derived from case data.
Sources
PM1 ModerateThe p.Val617Phe substitution is located in the JH2 pseudokinase domain (amino acids ~545-809), a well-established critical regulatory domain that mediates autoinhibition of JAK2 kinase activity. The JH2 domain is a recognized mutational hotspot for gain-of-function variants in myeloproliferative neoplasms, with multiple activating mutations described at this locus (e.g., K539L, R564Q, E695K). Position 617 is specifically identified as a residue whose alteration disrupts autoinhibitory interactions with the JH1 kinase domain activation loop. Details ▾Hide ▴
Evidence considered
- V617F located in JH2 pseudokinase domain — critical autoinhibitory region
- JH2 domain is a well-established mutational hotspot in MPN
- Multiple lines of evidence show JH2 disruption leads to constitutive kinase activation
- Residues 619-670 form one of three inhibitory regions within JH2
Sources
PM2 SupportingThe variant is present at very low frequency in gnomAD population databases: global AF 0.034% in v2.1 and 0.029% in v4.1, both below the 0.1% threshold for PM2. The maximum subpopulation frequency is 0.075% (Ashkenazi Jewish, v4.1). The presence of homozygotes (5 in v2.1, 17 in v4.1) is noted but is consistent with somatic clonal hematopoiesis in aging individuals rather than true germline homozygosity. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 0.034% (<0.1% threshold)
- gnomAD v4.1 AF = 0.029% (<0.1% threshold)
- Max subpop AF (Ashkenazi Jewish v4.1) = 0.075%
- grpmax FAF v2.1 = 0.000305
- v4.1 = 0.000277
Still missing
- Homozygote counts (5-17) are unusual for a rare germline variant — consistent with somatic clonal hematopoiesis but formal CHIP analysis not performed.
Sources
PP3 SupportingREVEL score of 0.881 is above the established deleterious threshold (≥0.75). Multiple in silico predictors support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.01). HCI Prior is not available for JAK2. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.881 (threshold ≥0.75 for deleterious)
- SpliceAI max delta = 0.01 (no predicted splice impact)
- HCI Prior not available for JAK2
Still missing
- BayesDel score 0.35869 is below typical thresholds — not used for PP3.
Sources
revelspliceai ↗
PP5 SupportingClinVar reports the variant as Pathogenic by 14 clinical laboratories and Likely pathogenic by 5 laboratories (ClinVar variation ID 14662). Multiple reputable clinical diagnostic laboratories have independently classified this variant as pathogenic, supporting a disease-causing role. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Pathogenic (14 clinical laboratories)
- ClinVar classification: Likely pathogenic (5 clinical laboratories)
- ClinVar classification: pathogenic (1 clinical laboratory)
Still missing
- Only 1 of 30 ClinVar submissions provides ACMG criteria — the remainder are asserted without criteria.
Sources
Not met · 4 · evaluated, threshold not reached
PS2 No de novo observation with confirmed maternity and paternity is documented for this variant in any source. The literature_pass flags PMID:25741868 for PS2 but this is the ACMG/AMP framework guideline paper, not a de novo case report. Details ▾Hide ▴
Evidence considered
- No de novo data in any reviewed source.
Still missing
- No de novo observation data available.
BA1 gnomAD global allele frequency is 0.034% (v2.1) and 0.029% (v4.1), far below the 1% threshold for BA1. Maximum subpopulation frequency is 0.075% (Ashkenazi Jewish, v4.1). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 0.034% (threshold >1%)
- gnomAD v4.1 AF = 0.029% (threshold >1%)
- Max subpop AF = 0.075% (threshold >1%)
Sources
BS1 gnomAD global allele frequency is 0.034% (v2.1) and 0.029% (v4.1), below the 0.3% threshold for BS1. Maximum subpopulation frequency is 0.075% (Ashkenazi Jewish, v4.1), also below the threshold. The variant is not observed at a frequency greater than expected for the disorder. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 0.034% (threshold >0.3%)
- gnomAD v4.1 AF = 0.029% (threshold >0.3%)
- Max subpop AF = 0.075% (threshold >0.3%)
Sources
BP4 REVEL score of 0.881 predicts a deleterious effect, contradicting the BP4 requirement that multiple lines of computational evidence suggest no impact on gene product. SpliceAI also shows no splicing impact, but the primary in silico metric (REVEL) strongly supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL = 0.881 (deleterious) — contradicts BP4 requirement for benign computational prediction.
Sources
revel
Not assessed · 9 · no assessment recorded
PS1 No alternate nucleotide change at c.1849 resulting in the same amino acid change (p.Val617Phe) has been identified in the case data. Only the G>T transversion is documented. Details ▾Hide ▴
Still missing
- No alternate nucleotide substitution at the same codon with established pathogenicity identified.
PP1 No segregation data available. PP1 requires co-segregation with disease in multiple affected family members. Details ▾Hide ▴
Still missing
- No family segregation data in case materials.
PP2 Gene-level constraint metrics (Z-score, pLI, missense depletion) for JAK2 are not evaluated in the case materials. PP2 requires a low rate of benign missense variation with missense variants as a common disease mechanism. While JAK2 gain-of-function missense variants are a well-known disease mechanism, formal constraint metric assessment is needed. Details ▾Hide ▴
Still missing
- JAK2 gene constraint metrics (gnomAD Z-score
- missense o/e) not evaluated.
PP4 Patient phenotype and family history data are not provided in the case materials. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
- No patient phenotype or family history provided.
BS2 BS2 requires observation of the variant in healthy adults with full penetrance expected at an early age. No such data are available in the case materials. Details ▾Hide ▴
Still missing
- No data on observation in healthy adults with expected full penetrance at early age.
BS4 No segregation data available. BS4 requires lack of segregation in affected family members. Details ▾Hide ▴
Still missing
- No family segregation data in case materials.
BP2 No phase data available. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant for recessive disorders. Details ▾Hide ▴
Still missing
- No trans/cis phase data available.
BP5 No data available regarding an alternate molecular basis for disease in a case harboring this variant. BP5 requires the variant to be found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- No data on alternate molecular basis in cases with this variant.
PS5 While ClinVar reports a 'criteria provided, single submitter' classification of Likely pathogenic from Labcorp/Invitae, the full ACMG criteria trail from that submission is not available for independent evaluation. PP5 is applied instead to capture the ClinVar pathogenic consensus. Details ▾Hide ▴
Evidence considered
- ClinVar review status: 'criteria provided
- single submitter' — limited independent verifiability.
Still missing
- ACMG criteria applied by the single criteria-providing submitter (SCV002307245) not accessible for review.
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_004972.3:c.1849G>T is a missense substitution (p.Val617Phe), not a null variant (nonsense, frameshift, or canonical splice). The variant does not fall into the default generic PVS1 null-variant buckets defined by ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense substitution at c.1849G>T resulting in p.Val617Phe
- variant_bucket='other'
- apply_generic_pvs1_framework=false per pvs1_variant_assessment.
Sources
PM3 N/ASkipped per instruction. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per instruction. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 candidate harvesting did not identify valid same-residue comparator variants. The pm5_candidates.json indicates eligibility for classic PM5 search could not be confirmed. Details ▾Hide ▴
Evidence considered
- pm5_mode='unknown'
- eligible_for_classic_pm5_search=false.
PM6 N/ANo de novo observation data available. PM6 requires a de novo observation with confirmed maternity and paternity. Details ▾Hide ▴
No further detail was recorded.
BS3 N/AFunctional evidence consistently demonstrates a gain-of-function pathogenic effect. BS3 requires well-established functional studies showing no deleterious effect — the opposite of what is observed. Details ▾Hide ▴
Evidence considered
- All functional studies demonstrate gain-of-function
- not benign effect.
BP1 N/AJAK2 disease mechanism is predominantly gain-of-function via activating missense variants, not loss-of-function via truncating variants. BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. Details ▾Hide ▴
Evidence considered
- JAK2 pathogenicity is driven by gain-of-function missense variants in the JH2 pseudokinase and JH1 kinase domains.
BP3 N/ASkipped per instruction. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ANo reputable source has classified this variant as benign. ClinVar classifications are exclusively pathogenic or likely pathogenic. Details ▾Hide ▴
Evidence considered
- All ClinVar classifications are Pathogenic or Likely pathogenic
- no benign assertions found.
BP7 N/ANM_004972.3:c.1849G>T is a missense variant (p.Val617Phe), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution — BP7 not applicable.
Identifiers
- Gene
- JAK2
- Transcript
- NM_004972.3
- Coding (HGVS c.)
- NM_004972.3:c.1849G>T
- Protein (HGVS p.)
- NP_004963.1:p.(Val617Phe)
- GRCh38
- chr9:5073770 G>T
- GRCh37
- chr9:5073770 G>T
- ClinVar
- 14662
- COSMIC
- COSV67569051
Gene diagram
Every interpreted variant in JAK2, mapped onto the exon structure of NM_004972.3. Select a row to find it on the plot.
JAK2NM_004972.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in JAK2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
471 / 1,605,918 alleles
AF 0.000293 · 17 homozygotes · FAF 0.000277
gnomAD v2.1
97 / 281,626 alleles
AF 0.000344 · 5 homozygotes · FAF 0.000305
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00029 · 471 / 1,605,918 alleles · 17 hom · FAF 0.00028
| Ashkenazi Jewish22 / 29,488 | 0.000751 hom |
| Middle Eastern3 / 6,062 | 0.00049 |
| European (non-Finnish)356 / 1,173,540 | 0.000313 hom |
| European (Finnish)19 / 63,542 | 0.00032 hom |
| South Asian27 / 90,798 | 0.0003 |
| African/African American19 / 74,656 | 0.000251 hom |
| Remaining individuals13 / 62,224 | 0.00021 |
| Admixed American7 / 59,922 | 0.00012 |
| East Asian5 / 44,774 | 0.00011 |
0 alternate alleles recorded in 1 other group: Amish.
gnomAD v2.1
AF 0.00034 · 97 / 281,626 alleles · 5 hom · FAF 0.00031
| Ashkenazi Jewish6 / 10,346 | 0.00058 |
| European (Finnish)14 / 24,872 | 0.000561 hom |
| European (non-Finnish)49 / 128,650 | 0.000383 hom |
| South Asian10 / 30,490 | 0.00033 |
| African/African American8 / 24,896 | 0.000321 hom |
| Admixed American6 / 35,276 | 0.00017 |
| East Asian3 / 19,928 | 0.00015 |
| Remaining individuals1 / 7,168 | 0.00014 |
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00029329; MAF= 0.02933%, 471/1605918 alleles, homozygotes = 17) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000746066; MAF= 0.07461%, 22/29488 alleles, homozygotes = 1); grpmax FAF= 0.0002771.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000344428; MAF= 0.03444%, 97/281626 alleles, homozygotes = 5) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000579934; MAF= 0.05799%, 6/10346 alleles, homozygotes = 0); grpmax FAF= 0.00030518.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0005979560774081322, 11/18396 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.881
- BayesDel
- 0.359
How the predictions were used
PP3 SupportingREVEL score of 0.881 is above the established deleterious threshold (≥0.75). Multiple in silico predictors support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.01). HCI Prior is not available for JAK2. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.881 (threshold ≥0.75 for deleterious)
- SpliceAI max delta = 0.01 (no predicted splice impact)
- HCI Prior not available for JAK2
Still missing
- BayesDel score 0.35869 is below typical thresholds — not used for PP3.
Sources
revelspliceai ↗
BP4 REVEL score of 0.881 predicts a deleterious effect, contradicting the BP4 requirement that multiple lines of computational evidence suggest no impact on gene product. SpliceAI also shows no splicing impact, but the primary in silico metric (REVEL) strongly supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL = 0.881 (deleterious) — contradicts BP4 requirement for benign computational prediction.
Sources
revel
BP7 N/ANM_004972.3:c.1849G>T is a missense variant (p.Val617Phe), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution — BP7 not applicable.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.881. BayesDel score = 0.35869.
7 paper records listed. 6 cited in the classification.
Cited in the classification
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PMID 15781101 ↗Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.Baxter EJ et al. · 2005 Mar 19-25Identified the acquired JAK2 V617F mutation in myeloproliferative disorders. This is one of the original discovery papers for JAK2 V617F, published simultaneously with James et al. (PMID:15793561) and others in 2005.→ PS4 Names this variant
Source detail
Location Abstract confirms V617F identification in MPN; full text not available for detailed review
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PMID 15793561 ↗A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.James C et al. · 2005 Apr 28Identified JAK2 V617F as a clonal, acquired G-to-T transversion at nucleotide 1849 in >80% of polycythaemia vera patients. The mutation confers constitutive STAT5 transcriptional activation in luciferase assays, transforms Ba/F3 and FDCP-EpoR cells to cytokine-independent growth, and induces erythrocytosis (haematocrit 60%) in a murine bone marrow transplant model. Wild-type JAK2 acts as a dominant negative, explaining selection for loss of heterozygosity at 9p.→ PS3 → PS4 → PM1 Names this variant
Source detail
one G-to-T mutation at nucleotide 1849 (in exon 12) leading to a substitution of valine to phenylalanine at position 617 (V617F)
Location Results p1144-1146; Figure 2a, 2e, 2f; Figure 3a-f; Figure 4
Context STAT5 luciferase reporter assay (gamma-2A cells), Ba/F3-EpoR and FDCP-EpoR cell transformation, murine bone marrow transplant (C57/B6)
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PMID 15858187 ↗A gain-of-function mutation of JAK2 in myeloproliferative disorders.Kralovics R et al. · 2005 Apr 28Identified a gain-of-function JAK2 V617F mutation in polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. The study linked V617F to 9p loss of heterozygosity and demonstrated constitutive kinase activity.→ PS4 Names this variant
Source detail
Location Title confirms V617F; full text not available for detailed review
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PMID 19543316 ↗SOCS-mediated downregulation of mutant Jak2 (V617F, T875N and K539L) counteracts cytokine-independent signaling.JAK2 V617F, along with T875N and K539L mutants, demonstrated constitutive activation of STAT1/3/5, ERK1/2, and p38 in HEK Flp-In-293 inducible cells. SOCS1 and SOCS3 were transcriptionally induced by V617F and recruited to the plasma membrane, leading to ubiquitin-proteasome-mediated degradation of the mutant protein. Constitutive Jak2-V617F activity is self-limiting through SOCS-mediated feedback, explaining the need for homozygous mutation or gene amplification to achieve full transformation.→ PS3 Names this variant
Source detail
The genetic mutation results in a valine to phenylalanine substitution in the pseudokinase domain of Jak2 at amino acid position 617, generating a constitutively active protein.
Location Abstract; Results p3070-3074; Figures 1-4
Context HEK Flp-In-293 inducible transfectants (with/without EpoR), HEL cells (homozygous V617F), SET2 cells (heterozygous V617F)
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PMID 21533163 ↗Analysis of Jak2 catalytic function by peptide microarrays: the role of the JH2 domain and V617F mutation.Peptide microarray analysis of JAK2 catalytic function demonstrated that the V617F mutation in the JH2 pseudokinase domain alters substrate specificity and enhances catalytic activity. The study provides direct biochemical evidence that the JH2 domain negatively regulates JH1 kinase activity and that V617F relieves this autoinhibition, altering the phosphopeptide signature compared to wild-type JAK2.→ PS3 → PM1 Names this variant
Source detail
Location Title and abstract; full text confirms variant-level analysis
Context Peptide microarray (PamGene) with recombinant JAK2 kinase domains
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PMID 29355841 ↗JAK2/IDH-mutant-driven myeloproliferative neoplasm is sensitive to combined targeted inhibition.Generated a JAK2/IDH-mutant-driven myeloproliferative neoplasm mouse model expressing Jak2V617F combined with mutant IDH1 or IDH2. The model demonstrated that combined JAK2 and IDH inhibition is effective in targeting MPN progression, confirming the central pathogenic role of Jak2V617F in disease maintenance and progression to bone marrow failure or AML.→ PS3 Names this variant
Source detail
Location Title and abstract; full text confirms Jak2V617F-driven model
Context Jak2V617F knock-in mouse model combined with mutant IDH1/IDH2; pharmacological inhibition studies
Other recorded publications
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PMID 12351625 ↗The pseudokinase domain is required for suppression of basal activity of Jak2 and Jak3 tyrosine kinases and for cytokine-inducible activation of signal transduction.Demonstrated that the JH2 pseudokinase domain negatively regulates Jak2 and Jak3 tyrosine kinase activity. Deletion of JH2 resulted in increased tyrosine phosphorylation and downstream signaling. This paper was published in 2002, predating the discovery of JAK2 V617F (2005), and does not mention or study the V617F variant.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
471 / 1,605,918 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
14 Pathogenic · 5 Likely pathogenic · 1 pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/14662/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-5073770-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-5073770-G-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-5073770-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004972.3%3Ac.1849…
- OncoKB ↗www.oncokb.org/gene/JAK2/V617F
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=146062192
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00029329; MAF= 0.02933%, 471/1605918 alleles, homozygotes = 17) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000746066; MAF= 0.07461%, 22/29488 alleles, homozygotes = 1); grpmax FAF= 0.0002771.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000344428; MAF= 0.03444%, 97/281626 alleles, homozygotes = 5) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000579934; MAF= 0.05799%, 6/10346 alleles, homozygotes = 0); grpmax FAF= 0.00030518.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0005979560774081322, 11/18396 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Pathogenic (14 clinical laboratories) and as Likely pathogenic (5 clinical laboratories) and as pathogenic (1 clinical laboratory). (ClinVarID = 14662)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.881. BayesDel score = 0.35869.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV67569051, n = 42916 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.