Submissions for variant NM_004972.4(JAK2):c.1849G>T (p.Val617Phe)

gnomAD frequency: 0.00036  dbSNP: rs77375493

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000015769	SCV000839961	pathogenic	Acquired polycythemia vera	2018-02-08	criteria provided, single submitter	clinical testing	The c.1849G>T (p.V617F) variant in the JAK2 gene is commonly reported as a somatic change in myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, primary myelofibrosis [PMID: 15781101, 15858187, 15837627, 19074595]. Recently, this variant has also been described as one of the most common drivers of age-related clonal hematopoiesis [PMID: 27563148]. The c.1849G>T (p.V617F) variant in the JAK2 gene is classified as a pathogenic somatic variant.
Fulgent Genetics, Fulgent Genetics	RCV000763621	SCV000894475	pathogenic	Primary familial polycythemia due to EPO receptor mutation; Acquired polycythemia vera; Budd-Chiari syndrome; Primary myelofibrosis; Acute myeloid leukemia; Thrombocythemia 3	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001092995	SCV001249759	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	JAK2: PM1, PM5, PM6, PS4:Moderate, PP4, PS3:Supporting
GeneDx	RCV001092995	SCV001825403	pathogenic	not provided	2024-09-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23425079, 25698270, 21120162, 21689158, 27777768, 28205126, 24381227, 16755940, 16293597, 29349042, 31721094, 28596259, 29641446, 23300178, 16156870, 16871278, 20182460, 24068492, 15781101, 19287384, 25157968, 24986690, 16081687, 16709929, 18394554, 24404189, 20339092, 22571758, 20631743, 23115274, 22818858, 22041374, 22829971, 22422826, 21160067, 19549988, 16341032, 26228487, 23537216, 23248577, 23057517, 19195039, 17596137, 17440677, 17194663, 16990759, 16904848, 16954506, 16926301, 15920007, 15858187, 15860661, 26556299, 19293426, 16762626, 15793561, 30944118, 33144682, 32581362, 31447099, 19327411, 27389715, 35861108, 37885353, 35150601)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001092995	SCV002307245	likely pathogenic	not provided	2024-11-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 617 of the JAK2 protein (p.Val617Phe). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant is a well-known somatic change that has been reported as a recurrent variant in many individuals affected with myeloproliferative disorders (PMID: 15920007, 15781101, 15858187, 15793561, 16603627). ClinVar contains an entry for this variant (Variation ID: 14662). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt JAK2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects JAK2 function (PMID: 15793561, 23535062). A different missense substitution at this codon (p.Val617Ile) has been reported to segregate with autosomal dominant hereditary thrombocytosis as a germline change in a single family (PMID: 22397670). Functional studies show that this variant results in constitutive kinase activation and cytokine hyper-responsiveness (PMID: 23535062, 22397670). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV000015769	SCV002320869	pathogenic	Acquired polycythemia vera	2022-01-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000015770	SCV002765070	pathogenic	Primary myelofibrosis	2022-11-24	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS3, PS4, PM1, PM5, PP4
Revvity Omics, Revvity	RCV000022627	SCV003831788	likely pathogenic	Thrombocythemia 3	2022-10-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000015770	SCV003835086	pathogenic	Primary myelofibrosis	2021-08-30	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000015769	SCV004806756	likely pathogenic	Acquired polycythemia vera	2024-09-02	criteria provided, single submitter	clinical testing
Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital	RCV001092995	SCV005328481	pathogenic	not provided	2024-02-26	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000763621	SCV005415821	pathogenic	Primary familial polycythemia due to EPO receptor mutation; Acquired polycythemia vera; Budd-Chiari syndrome; Primary myelofibrosis; Acute myeloid leukemia; Thrombocythemia 3		criteria provided, single submitter	clinical testing	PM2_Supporting+PS3+PS4+PM6_Supporting
OMIM	RCV000015769	SCV000036034	pathogenic	Acquired polycythemia vera	2014-08-07	no assertion criteria provided	literature only
OMIM	RCV000015770	SCV000036036	pathogenic	Primary myelofibrosis	2014-08-07	no assertion criteria provided	literature only
OMIM	RCV000015771	SCV000036037	pathogenic	Acute myeloid leukemia	2014-08-07	no assertion criteria provided	literature only
OMIM	RCV000015772	SCV000036038	risk factor	Budd-Chiari syndrome, susceptibility to, somatic	2014-08-07	no assertion criteria provided	literature only
OMIM	RCV000022627	SCV000043916	pathogenic	Thrombocythemia 3	2014-08-07	no assertion criteria provided	literature only
OMIM	RCV000022628	SCV000043917	affects	Primary familial polycythemia due to EPO receptor mutation	2014-08-07	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003803	SCV001162249	likely pathogenic	Primary myelofibrosis; Splenomegaly		no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003804	SCV001162250	pathogenic	Polycythemia		no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000427081	SCV001162251	pathogenic	Myeloproliferative disorder		no assertion criteria provided	research
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001092995	SCV002036319	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001092995	SCV002037447	pathogenic	not provided		no assertion criteria provided	clinical testing
Molecular Diagnostics Laboratory, University of Rochester Medical Center	RCV000015769	SCV004175181	pathogenic	Acquired polycythemia vera		no assertion criteria provided	provider interpretation
PreventionGenetics, part of Exact Sciences	RCV004751211	SCV005351640	pathogenic	JAK2-related disorder	2024-04-30	no assertion criteria provided	clinical testing	The JAK2 c.1849G>T variant is predicted to result in the amino acid substitution p.Val617Phe. This variant has been reported to be present in almost all patients with polycythemia vera and more than half of those with essential thrombocytosis and primary myelofibrosis (Vassiliou 2016. PubMed ID: 27563148). Somatic c.1849G>T variants have been reported in myeloproliferative neoplasms (Ortmann et al. 2015. PubMed ID: 25671252; Rumi et al. 2014. PubMed ID: 24986690). This variant is reported in 0.058% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic.