Submissions for variant NM_139276.3(STAT3):c.1919A>T (p.Tyr640Phe)

gnomAD frequency: 0.00001  dbSNP: rs769031989

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414550	SCV000490834	pathogenic	not provided	2016-10-31	criteria provided, single submitter	clinical testing	The Y640F variant has been observed as a somatic variant in multiple individuals with lymphocytic leukemia (Koskela et al., 2012; Kristensen et al., 2014; Tanahashi et al., 2016). However, it has not been published in association with Hyper-IgE syndrome to our knowledge. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Y640F is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the critical SH2 domain that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, functional studies have shown that Y640F is a gain-of-function variant that leads to increased cell selection (Koskela et al., 2012; Küçük et al., 2015). Therefore, we consider the variant to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420711	SCV000699916	uncertain significance	not specified	2024-08-22	criteria provided, single submitter	clinical testing	Variant summary: STAT3 c.1919A>T (p.Tyr640Phe) results in a conservative amino acid change located in the Src homology 2 (SH2) domain (IPR000980) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.9e-06 in 1614036 control chromosomes (gnomAD). c.1919A>T has been reported in the literature in individuals affected with features of Autoimmune Disease, Multisystem, Infantile-Onset, 1 (Hadjadj_2019, Leiding_2023). These data indicate that the variant may be associated with disease. The p.Tyr640Phe variant has also been frequently reported as a GoF somatic mutation in individuals affected with lymphoid neoplasms and other cancer phenotypes (see e.g. Pilati_2011, Koskela_2012, Jerez_2012, Jerez_2013, Crescenzo_2015, and in the COSMIC database). Additionally, the variant has been reported in one patient as a somatic variant in a T-lymphocyte subpopulation, which resulted in an aberrant cytokine production by the aberrant T-cell clone with consequential secondary hypereosinophilia; of note, this patient also had a high level of IgE, suggesting that somatic c.1919A>T also may be associated with hyper IgE phenotype (Walker_2016). Multiple functional studies demonstrated that the variant results in a highly increased transcriptional activity of STAT3 even in the absence of IL-6 stimulation, demonstrating that it is a gain-of-function mutation (e.g. Pilati_2011, Koskela_2012, Crescenzo_2015, Bahal_2019, Jagle_2019, Parri_2020, Kasembeli_2023, Brandstoetter_2023). The following publications have been ascertained in the context of this evaluation (PMID: 22591296, 25873174, 21690253, 26702067, 23926297, 22859607, 31737384, 30940614, 32231398, 31770611, 36240433, 36228738, 36630607). ClinVar contains an entry for this variant (Variation ID: 372521). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001036591	SCV001199964	uncertain significance	Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function	2023-09-25	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 640 of the STAT3 protein (p.Tyr640Phe). 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 missense change has been observed in individual(s) with Evans syndrome as a germline variant. It is also a common somatic variant observed in individuals with T cell large granular lymphocytic leukemia (PMID: 22591296, 30940614). ClinVar contains an entry for this variant (Variation ID: 372521). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt STAT3 protein function. Experimental studies have shown that this missense change affects STAT3 function (PMID: 22591296, 25873174, 29162862, 29180260, 31771617). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Department Of Pathology & Laboratory Medicine, University Of Pennsylvania	RCV003448978	SCV004176808	pathogenic	Malignant lymphoma, large B-cell, diffuse	2023-12-04	no assertion criteria provided	clinical testing	Pre-therapy specimen.
Department of Clinical Pathology, School of Medicine, Fujita Health University	RCV004559046	SCV004218249	pathogenic	EBV-positive nodal T- and NK-cell lymphoma		no assertion criteria provided	research