The JAK2 NM_004972.4:c.1849G>T (NP_004963.1:p.(Val617Phe)) missense variant has previously been reported in somatic cancers (COSMIC; COSV67569051, n = 42916 times). Experimental evidence: Independent cellular, recombinant-protein, and murine assays show constitutive signaling, approximately threefold higher kinase activity (493±19 vs 150±9), and disease phenotypes. Based on available guidelines, this variant is considered to be Pathogenic.
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.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.JAK2 encodes a signaling protein that helps cells respond to cytokines and growth factors, including signals that regulate the production of blood cells. Abnormal JAK2 activity is associated with inflammatory diseases and blood disorders such as polycythemia vera, essential thrombocythemia, and myelofibrosis. JAK2 acts as an oncogene and contributes to some leukemias, lymphomas, and other cancers by driving persistent cell-growth signaling.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at strong strength: independent cellular, recombinant-protein, and murine assays show constitutive signaling, approximately threefold higher kinase activity (493±19 vs 150±9), and disease phenotypes.
Met: 40/45 cases versus 0/15 controls gives a continuity-corrected OR 228.27 (95% CI 11.90-4377.56), exceeding the >5.0 threshold with the CI excluding 1.0.
Met at moderate strength: REVEL 0.881 meets the >=0.773 PP3 moderate threshold but remains below the >=0.932 strong threshold.
No benign criterion marked as applied in the recorded assessment.
Pathogenic: PS3 strong and PS4 strong satisfy the generic ACMG/AMP rule for two strong pathogenic criteria, with PP3 moderate additional support.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 471 / 1,605,918 alleles. Recorded AF 0.00029329. Recorded homozygote count 17.
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.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0005979560774081322, 11/18396 alleles, homozygotes = 0).
Recorded REVEL score: 0.881. Refer to the recorded PP3/BP4 rationale for interpretation.
17 Pathogenic · 4 Likely pathogenic · 1 pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV67569051, n = 42916 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 9 not met · 11 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PS4 is met at strong strength because multiple full-text studies report substantial enrichment of exact JAK2 p.Val617Phe among affected myeloproliferative-neoplasm patients versus controls, including a computed OR 228.27 (95% CI 11.90-4377.56).
PP4, BP5 are not assessed because the bundle lacks the required patient-specific phenotype/family-history or alternate-molecular-basis evidence.
PP5 and BP6 are not met because the exact ClinVar audit reports zero expert-panel submissions; ordinary laboratory and aggregate classifications are excluded by the specified rule.
The missense consequence determines the REVEL-only path for both criteria; the same prediction is not double-counted across PP3 and BP4.
REVEL 0.881 supports PP3 at moderate strength and does not support BP4; SpliceAI is excluded for this missense variant.
No criteria match.
PS3 is met at strong strength. Multiple independent, variant-specific functional studies provide concordant evidence across recombinant protein, engineered cell, patient-derived cell, hematopoietic colony, and murine systems. JAK2 V617F shows approximately threefold higher catalytic activity than wild-type JAK2 JH1-JH2 (493±19 versus 150±9 relative activity per pmol protein) in a recombinant kinase assay; constitutive phosphorylation of STAT5, STAT3, STAT1, ERK1/2, and p38 is observed in patient-derived HEL cells; cytokine-independent proliferation/survival and increased STAT5 phosphorylation are demonstrated in BaF3 and UT-7/TPO cells with appropriate cytokine-dependent controls; and expression in a mouse transplantation model produces erythrocytosis. These orthogonal assays directly test the specified variant and include wild-type, cytokine-stimulation, cytokine-withdrawal, inhibitor, or disease-model comparisons, supporting a reproducible gain-of-function/damaging effect on JAK2 function.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
The exact JAK2 c.1849G>T (p.Val617Phe) variant was found in 40/45 polycythemia vera patients and 0/15 controls in PMID:15793561. Treating the zero control cell with the Haldane-Anscombe 0.5 correction, the computed OR is 228.27 with a 95% CI of 11.90-4377.56; the required comparison is OR > 5.0 and the CI excludes 1.0 (228.27 > 5.0? yes; 11.90-4377.56 includes 1.0? no). Independent full-text extracts also report 71/73, 29/51, and 8/16 affected patients versus 90 controls in PMID:15781101, and 117/244 affected patients with absence from healthy controls in PMID:15858187. These are case-control prevalence comparisons even where an odds ratio was not printed, and the exact variant was verified in the full-text extracts.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
The variant is a missense SNV, p.(Val617Phe), so the governing generic rule selects the REVEL path only and excludes SpliceAI from PP3/BP4. REVEL is 0.881, meeting the generic PP3 moderate threshold of >= 0.773 but not the strong threshold of >= 0.932. This supports PP3 at moderate strength. The calibration threshold is from the ClinGen SVI REVEL calibration by Pejaver et al. 2022 (PMID:36413997).
Missense variant -> REVEL only. ... PP3 (moderate): >= 0.773 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
PM2 is not met. The variant is present in population databases at AF 0.00029329 in gnomAD v4.1 (471/1,605,918 alleles), AF 0.000344428 in gnomAD v2.1 all-comers (97/281,626 alleles), AF 0.000335118 in gnomAD v2.1 non-cancer exomes (79/235,738 alleles), and AF 0.000372432 in gnomAD v3.1 non-cancer genomes (55/147,678 alleles). The all-comers and non-cancer frequencies exceed the supplied PM2 supporting cutoff of <=0.0001, so the variant is neither absent nor at an extremely low frequency under the case's generic PM2 rule.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
The exact ClinVar record has pathogenic and likely pathogenic laboratory submissions, but the audit reports zero expert-panel submissions. Under the required generic rule, ordinary laboratory submissions, aggregate labels, and non-expert assertions cannot trigger PP5.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. The highest relevant all-comers frequency is gnomAD v4.1 AF 0.00029329 (471/1,605,918 alleles), and the highest reported population frequency is Ashkenazi Jewish AF 0.000746066; both are far below the generic ACMG/AMP 5% threshold. The non-cancer subsets are also far below this threshold: gnomAD v2.1 non-cancer exomes AF 0.000335118 (79/235,738 alleles) and gnomAD v3.1 non-cancer genomes AF 0.000372432 (55/147,678 alleles).
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is not met. The all-comers gnomAD v4.1 AF is 0.00029329 and the highest population AF is 0.000746066, while the generic default BS1 threshold is 0.01; the non-cancer frequencies are similarly low (v2.1 exomes 0.000335118; v3.1 genomes 0.000372432). These data do not show an allele frequency greater than expected for the relevant disorder, and no maximum-credible-frequency calculation is needed because the observed frequencies are well below the default threshold. The variant is a known somatic JAK2 V617F mutation, so germline disease-prevalence or penetrance assumptions should not be used to manufacture a stronger benign frequency claim.
Allele frequency is greater than expected for disorder.
BS3 is not met. No reviewed well-established assay demonstrates that JAK2 p.Val617Phe has no damaging effect on protein function or splicing. Instead, the variant produces concordant constitutive signaling, increased catalytic activity, cytokine-independent growth or survival, altered hematopoietic behavior, and disease phenotypes across orthogonal cellular, biochemical, and in vivo models. The available functional evidence therefore contradicts a benign functional interpretation rather than satisfying BS3.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
BP1 is not supported because the supplied evidence demonstrates a recurrent activating missense mechanism for JAK2, including p.Val617Phe, rather than a gene for which disease is primarily caused by truncating variants.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 requires observation of the evaluated variant in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritance pattern. PMID:15858187 reports JAK2 p.Val617Phe as a somatic mutation and describes homozygosity associated with 9p loss of heterozygosity, but does not report a distinct pathogenic variant in trans or a pathogenic variant in cis with p.Val617Phe. Homozygosity for the same somatic variant does not satisfy either BP2 path.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The variant is a missense SNV, p.(Val617Phe), so the governing generic rule selects the REVEL path only and excludes SpliceAI from PP3/BP4. REVEL is 0.881, which does not meet the generic BP4 supporting threshold of <= 0.29; therefore BP4 is not met. The low SpliceAI max delta of 0.013 cannot substitute for the non-supportive REVEL result in a missense variant. The calibration threshold is from the ClinGen SVI REVEL calibration by Pejaver et al. 2022 (PMID:36413997).
Missense variant -> REVEL only. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The exact ClinVar record contains no qualifying expert-panel benign or likely-benign classification. Available submissions are pathogenic or likely pathogenic laboratory assertions, and ordinary laboratory submissions or aggregate labels cannot trigger BP6 under the required generic rule.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The case evidence establishes JAK2 p.Val617Phe itself, but does not document a previously established pathogenic variant producing the same amino-acid change through a different nucleotide change. The available evidence therefore cannot satisfy the specific PS1 comparator requirement.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
PS2 cannot be assessed because the available evidence does not document a disease-affected proband with no family history, confirmed maternity, and confirmed paternity for this variant. The required trio and clinical-context information are absent.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
JAK2 p.Val617Phe lies in the JH2 pseudokinase domain, and the literature establishes JH2 as a functionally important regulatory domain. However, vcep_materials.json has no JAK2 domain table, and the supplied evidence does not establish that the relevant domain lacks benign variation; the complete PM1 requirement therefore cannot be confirmed.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
The supplied evidence does not provide a validated, previously established pathogenic missense variant at JAK2 residue 617 that differs from p.Val617Phe. A literature title mentions V617I, but no corresponding extract or source-registry record establishes that comparator as pathogenic, so PM5 cannot be applied.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
PM6 cannot be assessed because no case-specific evidence documents an assumed de novo occurrence or parental testing showing absence of the variant in either parent. The available literature describes population or disease cohorts rather than this variant's inheritance in a family.
Assumed de novo, but without confirmation of paternity and maternity.
PP1 cannot be assessed because no affected family members, informative meioses, variant-positive relatives, or phenotype-consistent segregation data are documented for this variant. The available evidence does not provide a family segregation analysis.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The evidence supports a disease mechanism involving recurrent activating JAK2 missense variation, including p.Val617Phe, but it does not provide a gene-level assessment demonstrating both a low rate of benign missense variation and that missense variants are a common disease mechanism under the PP2 definition.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The available case evidence identifies the molecular variant but does not provide a patient-specific phenotype or family history that can be evaluated for high specificity to a single-gene disease. The criterion therefore cannot be assessed from the available evidence.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 is not assessed. gnomAD reports homozygotes (17 in v4.1 all-comers; 4 in v2.1 non-cancer exomes; 1 in v3.1 non-cancer genomes), but these databases do not establish that the individuals were healthy adults with a germline JAK2 V617F variant. JAK2 V617F is a recognized acquired somatic mutation, and the observed population calls may reflect clonal hematopoiesis or other somatic mosaicism rather than constitutional homozygosity. Therefore the available evidence cannot satisfy the BS2 requirement for observation in a healthy adult with full early-age penetrance expected.
BS2
BS4 cannot be assessed because no affected family members have documented negative testing for this variant. No family pedigree, phenotype assessment, or non-segregation analysis is available, so the phenocopy and multiple-pathogenic-variant caveats cannot be evaluated.
Lack of segregation in affected members of a family.
The available evidence does not document that this exact variant was found in a case with an alternate molecular basis for disease. No patient-level alternate molecular diagnosis is available for assessment of BP5.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_004972.4:c.1849G>T in JAK2 is a missense substitution predicted to produce NP_004963.1:p.(Val617Phe). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for JAK2, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM3 is limited to recessive disorders and requires the evaluated variant to be detected in trans with a pathogenic variant, with phase established by parental or offspring testing. The available variant-specific literature identifies JAK2 p.Val617Phe as an acquired somatic mutation in myeloproliferative neoplasms, not as an allele causing a recessive inherited disorder; therefore PM3 is not applicable. The observed homozygosity in cells with 9p loss of heterozygosity reflects somatic clonal evolution and is not evidence for a recessive affected proband carrying this variant in trans with a pathogenic germline allele.
For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_004972.4:c.1849G>T in JAK2 is a missense substitution predicted to produce NP_004963.1:p.(Val617Phe). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for JAK2, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_004972.4:c.1849G>T in JAK2 is a missense substitution predicted to produce NP_004963.1:p.(Val617Phe). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for JAK2, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_004972.4:c.1849G>T in JAK2 is a missense substitution predicted to produce NP_004963.1:p.(Val617Phe). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for JAK2, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in JAK2, mapped onto the exon structure of NM_004972.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| 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 |
| 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 |
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.
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.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0005979560774081322, 11/18396 alleles, homozygotes = 0).
The variant is a missense SNV, p.(Val617Phe), so the governing generic rule selects the REVEL path only and excludes SpliceAI from PP3/BP4. REVEL is 0.881, meeting the generic PP3 moderate threshold of >= 0.773 but not the strong threshold of >= 0.932. This supports PP3 at moderate strength. The calibration threshold is from the ClinGen SVI REVEL calibration by Pejaver et al. 2022 (PMID:36413997).
Missense variant -> REVEL only. ... PP3 (moderate): >= 0.773 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is a missense SNV, p.(Val617Phe), so the governing generic rule selects the REVEL path only and excludes SpliceAI from PP3/BP4. REVEL is 0.881, which does not meet the generic BP4 supporting threshold of <= 0.29; therefore BP4 is not met. The low SpliceAI max delta of 0.013 cannot substitute for the non-supportive REVEL result in a missense variant. The calibration threshold is from the ClinGen SVI REVEL calibration by Pejaver et al. 2022 (PMID:36413997).
Missense variant -> REVEL only. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_004972.4:c.1849G>T in JAK2 is a missense substitution predicted to produce NP_004963.1:p.(Val617Phe). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for JAK2, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
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.
A single point mutation (Val617Phe) was identified in JAK2 in 71 (97%) of 73 patients with polycythaemia vera, 29 (57%) of 51 with essential thrombocythaemia, and eight (50%) of 16 with idiopathic myelofibrosis.
Location Summary, Findings; Results, paragraphs 1–3; Table 1; Table 2
Context Cohort of 140 patients with myeloproliferative disorders and 90 controls; bidirectional sequencing of JAK2 coding exons, allele-specific PCR, loss-of-heterozygosity analysis, FISH, SNP-array analysis, and mutation testing of individual haematopoietic colonies.
the V617F substitution was found in 40 out of 45 polycythaemia vera patients, but not in the 15 controls.
Location Results, paragraphs describing sequencing and cell-lineage analysis; Figures 2–4
Context Sequencing of JAK2 exon 12 in polycythaemia vera, control, and secondary erythrocytosis cohorts; lineage-specific DNA analysis; STAT5 luciferase assay in JAK2-deficient gamma-2A cells; retroviral JAK2 expression in factor-dependent cell lines; mouse bone-marrow transplantation model.
V617F is a somatic mutation present in hematopoietic cells.
Location Abstract; Results sections “9pLOH and a G→T mutation in the coding region of JAK2,” “Identification of a somatic mutation in myeloproliferative disorders,” and “Proliferative and survival advantage afforded by V617F”; Table 1; Figure 4
Context Cohort of 244 patients with myeloproliferative disorders, including 128 with polycythemia vera, 93 with essential thrombocythemia, and 23 with idiopathic myelofibrosis; sequencing of JAK2 cDNA and genomic DNA from hematopoietic and nonhematopoietic tissues; functional assays in JAK2-transfected BaF3 and UT-7/TPO cells measuring proliferation, viability, and JAK2/STAT5 phosphorylation.
In HEL cells, patient-derived leukemia cells naturally carrying the Jak2-V617F mutation, constitutive phosphorylation of STAT5, STAT3, STAT1, Erk1/2 and p38 can also be observed.
Location Results, section "Constitutively active Jak2 mutants show a reduced expression," paragraph discussing HEL cells
Context Patient-derived HEL and SET2 leukemia cell lines, inducible HEK-cell JAK2 expression models, western blotting, quantitative PCR, co-immunoprecipitation, confocal microscopy, ubiquitination and proteasome-inhibition assays, and SOCS1/SOCS3 siRNA experiments.
mutation V617F partially relieves the inhibition of the JH2 domain on catalytic activity but has limited effect on substrate preference
Location Results, “Activity of the proteins”; Results, “Catalytic efficiency of JAK2 kinase domain”; Discussion and Conclusion
Context Recombinant HIS-tagged JAK2 JH1-JH2 wild-type, JH1-JH2 V617F, and JH1 proteins expressed in Sf9 cells; activity and substrate preference measured using PamChip tyrosine-kinase peptide microarrays with 144 peptides and custom peptide arrays.
These data indicate that concurrent JAK2 and IDH1/2 mutations cooperate to drive a lethal, transplantable MPN with impaired differentiation in vivo.
Location Results, "JAK2V617F and neomorphic IDH1/IDH2 mutations cooperate in vivo to drive progressive MPN," final sentence of the paragraph
Context Conditional murine Jak2V617F models combined with IDH1R132H or Idh2R140Q alleles, hematopoietic stem/progenitor-cell transplantation studies, inhibitor treatment assays, RNA sequencing, metabolomic analysis, and methylcellulose assays using patient-derived JAK2V617F/IDH2R140Q samples.
JH2Δ-Jak2 induced significantly increased, constitutive activation of STAT1 in the absence of IFN-α, and this activity was not further increased by IFN-α stimulation.
Results, Fig. 6B; Results, Fig. 7; Discussion
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
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.
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.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0005979560774081322, 11/18396 alleles, homozygotes = 0).
This variant has been reported in ClinVar as Pathogenic (17 clinical laboratories) and as Likely pathogenic (4 clinical laboratories) and as pathogenic (1 clinical laboratory). (ClinVarID = 14662)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.881. BayesDel score = 0.35869.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV67569051, n = 42916 times).
This variant does not lie in a statistically significant hotspot.