rs769031989

chr17-42322464-T-Achr17-42322464-T-Cchr17-42322464-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The NM_139276.3(STAT3):c.1919A>T(p.Tyr640Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y640Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: STAT3 NM_139276.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 8.02

Genes affected

STAT3 (HGNC:11364): (signal transducer and activator of transcription 3) The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein is activated through phosphorylation in response to various cytokines and growth factors including IFNs, EGF, IL5, IL6, HGF, LIF and BMP2. This protein mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis. The small GTPase Rac1 has been shown to bind and regulate the activity of this protein. PIAS3 protein is a specific inhibitor of this protein. This gene also plays a role in regulating host response to viral and bacterial infections. Mutations in this gene are associated with infantile-onset multisystem autoimmune disease and hyper-immunoglobulin E syndrome. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_139276.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, STAT3
• PP5: Variant 17-42322464-T-A is Pathogenic according to our data. Variant chr17-42322464-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372521.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT3	NM_139276.3	c.1919A>T	p.Tyr640Phe	missense_variant	21/24	ENST00000264657.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT3	ENST00000264657.10	c.1919A>T	p.Tyr640Phe	missense_variant	21/24	1	NM_139276.3	A1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461818 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000301 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Malignant lymphoma, large B-cell, diffuse Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department Of Pathology & Laboratory Medicine, University Of Pennsylvania

Dec 04, 2023

Pre-therapy specimen. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 31, 2016

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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 28, 2023

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 4e-06 in 251474 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1919A>T has been reported in the literature in a child affected with Evans syndrome, a rare autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia (Hadjadj_2019). Germline STAT3 gain-of-function (GoF) variants are known to be linked to poly-autoimmunity and lymphoproliferation with variable expressivity and incomplete penetrance (see e.g. Jagle_2019), a phenotype also known as infantile-onset multisystem autoimmune disease-1 (ADMIO1; see in OMIM). The p.Tyr640Phe variant has 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). To our knowledge, this variant has not been reported in the germline state in any patient with autosomal dominant Hyper-IgE recurrent infection syndrome 1 (HIES1), which is caused by loss-of-function (LoF) germline variants in the STAT3 gene (see e.g. in PMID 22751495). However, this 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). The following publications have been ascertained in the context of this evaluation (PMID: 31737384, 25873174, 30940614, 31770611, 22859607, 23926297, 22591296, 32231398, 21690253, 26702067, 36240433). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

STAT3 gain of function;C4721531:Hyper-IgE recurrent infection syndrome 1, autosomal dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 25, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	29
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.92	D;.;D;D;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.74	D;D;D;D;D
MetaSVM	Uncertain	-0.038	T
MutationAssessor	Benign	1.3	L;L;.;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.0	D;.;D;.;D
REVEL	Uncertain	0.64
Sift	Benign	0.15	T;.;T;.;T
Sift4G	Benign	0.32	T;T;T;T;T
Polyphen		0.98	D;.;.;D;D
Vest4		0.56
MutPred		0.89		Loss of ubiquitination at K642 (P = 0.0603);Loss of ubiquitination at K642 (P = 0.0603);.;Loss of ubiquitination at K642 (P = 0.0603);Loss of ubiquitination at K642 (P = 0.0603);
MVP		0.82
MPC		2.4
ClinPred		0.92	D
GERP RS		4.6
Varity_R		0.75
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs769031989; hg19: chr17-40474482; COSMIC: COSV52882807; COSMIC: COSV52882807;