Submissions for variant NM_139276.3(STAT3):c.2050G>C (p.Gly684Arg)

gnomAD frequency: 0.00002  dbSNP: rs780466766

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001057008	SCV001221477	uncertain significance	Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function	2023-04-29	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 852410). This missense change has been observed in individual(s) with acute myeloid leukemia (PMID: 29296824). This variant is present in population databases (rs780466766, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 684 of the STAT3 protein (p.Gly684Arg).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230627	SCV003928695	likely benign	not specified	2023-04-14	criteria provided, single submitter	clinical testing	Variant summary: STAT3 c.2050G>C (p.Gly684Arg) results in a non-conservative amino acid change located in the SH2 domain (IPR035855) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251470 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 50 fold of the estimated maximal estimated allele frequency for a pathogenic variant in STAT3 causing Hyper IgE Syndrome phenotype (2.2e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2050G>C has been reported in the literature in an individual affected with acute myeloid leukemia, however, co-occurrence with a pathogenic variant was also reported in this individual (TP53 c.844C>T, p.R282W), providing supporting evidence for a benign role (Morgan_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.