Submissions for variant NM_139276.3(STAT3):c.1981G>T (p.Asp661Tyr)

gnomAD frequency: 0.00001  dbSNP: rs747639500

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193229	SCV001361953	uncertain significance	not specified	2024-06-13	criteria provided, single submitter	clinical testing	Variant summary: STAT3 c.1981G>T (p.Asp661Tyr) results in a non-conservative amino acid change located in the SH2 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251488 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1981G>T has been reported in the literature in multiple individuals as a somatic occurrence in association with cancer, predominantly large granular lymphocyte leukemia (e.g. de Araujo_2019, Ishida_2014, Jerez_2012, Koskela_2012, Laurent_2020). However, no publications were found citing the variant in association with Hyper IgE Syndrome. Functional studies found the variant to play a role in cancer development and described it as an activating, gain-of-function mutation (Chen_2017, Cording_2022). However, the implications of these findings in relation to Hyper IgE syndrome cannot be concluded. This codon, D661, is indicated to be a mutational hotspot for cancers (COSMIC, de Araujo_2019). Variants in nearby codons, M660R, M660T, and I665N, have been reported in association with Hyper IgE syndrome (de Araujo_2019, HGMD). The following publications have been ascertained in the context of this evaluation (PMID: 28356514, 33579790, 24350896, 22859607, 22591296, 31774495, 31558678, 31717342). ClinVar contains an entry for this variant (Variation ID: 928790). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002560162	SCV003482361	uncertain significance	Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 661 of the STAT3 protein (p.Asp661Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has been observed as a somatic variant associated with leukemia (PMID: 24350896, 28977911, 24995504), however, it has not been observed as a germline variant in individuals with STAT3-related conditions. ClinVar contains an entry for this variant (Variation ID: 928790). 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 expected to disrupt STAT3 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects STAT3 function (PMID: 28356514, 30910759). 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 Clinical Pathology, School of Medicine, Fujita Health University	RCV004559917	SCV004218248	pathogenic	EBV-positive nodal T- and NK-cell lymphoma		no assertion criteria provided	research