NM_139276.2:c.1940A>T

STAT3 · NP_644805.1:p.(Asn647Ile) · NM_139276.2

GRCh37: chr17:40474461 T>A · GRCh38: chr17:42322443 T>A

Gene: STAT3 Transcript: NM_139276.2

Final call

VUS

PM1 moderate PM2 supporting

Variant details

Gene

STAT3

Transcript

NM_139276.2

Protein

NP_644805.1:p.(Asn647Ile)

gnomAD AF

1.2389946301972728e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_139276.2:c.1940A>T (p.Asn647Ile) in STAT3 was assessed using generic ACMG/AMP 2015 criteria (PMID:25741868). No CSPEC/VCEP framework is available for STAT3.

This missense variant is located in the SH2 domain (residues 583–688), a well-established mutational hotspot where numerous pathogenic variants have been identified in both germline hyper-IgE syndrome and somatic lymphoproliferative disorders, satisfying PM1 at moderate strength.

The variant is absent from gnomAD v2.1 (0/251,490 alleles) and extremely rare in gnomAD v4.1 (2/1,614,212 alleles; AF=1.24×10⁻⁶), satisfying PM2 at supporting strength.

In silico predictors do not reach consensus for pathogenicity (REVEL 0.359; BayesDel −0.126; SpliceAI 0.00), and do not reach consensus for benign impact either — PP3 and BP4 are not met.

ClinVar classification is conflicting: two clinical laboratories report Uncertain Significance and one reports Pathogenic. No expert panel review is available. PP5 is not met due to conflicting interpretations, and BP6 is not met as no submitter classifies the variant as Benign.

Several criteria (PS3, PS4) could not be fully assessed because variant-specific evidence from cited publications could not be confirmed without full-text access. PMID:27345172 ('Distinct mutations at the same positions of STAT3 cause either loss or gain of function') is of particular relevance for functional evidence but has no abstract or full-text available in the evidence packet.

With 1 moderate criterion (PM1) and 1 supporting criterion (PM2) met, and no benign criteria met, the variant does not reach the Likely Pathogenic threshold (requires at least 1 strong + 1–2 moderate, or 3 moderate, or 2 moderate + 2 supporting). The variant is classified as a Variant of Uncertain Significance (VUS) according to generic ACMG/AMP 2015 combination rules.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 applies to null variants (nonsense, frameshift, canonical splice ±1,2). NM_139276.2:c.1940A>T is a missense variant (p.Asn647Ile) and does not fall into any PVS1 null-variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not assessed	PS1 requires a different nucleotide change at the same codon leading to the same missense change (N647I) that has been previously classified as pathogenic. No such alternate nucleotide variant was identified in the available evidence.
PS2	Not met	No report of de novo occurrence with confirmed maternity and paternity was identified for NM_139276.2:c.1940A>T in any ClinVar submission or reviewed literature.	clinvar
PS3	Not assessed	Well-established in vitro/in vivo functional studies are required for PS3. Several papers (PMID:22859607, PMID:27345172, PMID:31717342) discuss STAT3 SH2 domain functional characterization, but full-text could not be accessed to confirm variant-specific functional data for p.Asn647Ile (N647I). Abstract-level evidence from PMID:22859607 describes STAT3 mutations in SH2 domain affecting activation and gene regulation, but does not name N647I specifically. OncoKB annotates this variant as 'Likely Oncogenic' in somatic context, but this does not substitute for germline PS3 evidence.	oncokb
PS4	Not met	PS4 requires that prevalence of the variant in affected individuals is significantly increased compared to controls. While gnomAD shows extreme rarity (2/1,614,212 alleles in v4.1), no variant-specific case counts in a defined germline disease cohort (e.g., hyper-IgE syndrome or STAT3-related immunodeficiency) were confirmed from full-text review. The 28 somatic occurrences in COSMIC are not informative for germline PS4. Without confirmed proband counts from the literature, PS4 cannot be applied.	gnomad_v4
PS5	N/A	PS5 is not part of the standard ACMG/AMP 2015 criteria (PMID:25741868). The related criterion PS1 (same amino acid change from a different nucleotide) was separately assessed.
PM1	Met	c.1940A>T (p.Asn647Ile) is located in the STAT3 Src homology 2 (SH2) domain (UniProt residues 583–688). The SH2 domain is a well-established mutational hotspot where numerous pathogenic missense variants have been documented in both germline hyper-IgE syndrome and somatic lymphoproliferative disorders. Multiple publications describe clustering of disease-associated missense mutations in the STAT3 SH2 domain.	oncokb PMID:22859607
PM2	Met	NM_139276.2:c.1940A>T is absent from gnomAD v2.1 (0/251,490 alleles) and extremely rare in gnomAD v4.1 (2/1,614,212 alleles; AF=1.24×10⁻⁶; grpmax FAF=2.8×10⁻⁷). Both are well below the 0.1% PM2 threshold. The variant is also absent from gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No alternate missense change at codon 647 with a pathogenic classification was identified as a PM5 comparator. The automated PM5 candidate harvest returned zero same-residue candidates.
PM6	Not met	PM6 requires a de novo observation without confirmation of both maternity and paternity. No de novo report, with or without confirmed parentage, was identified for NM_139276.2:c.1940A>T in ClinVar submissions or reviewed literature.	clinvar
PP1	Not met	PP1 requires cosegregation of the variant with disease in multiple affected family members. No published pedigree with cosegregation data for NM_139276.2:c.1940A>T was identified.
PP2	Not assessed	PP2 requires a missense variant in a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. STAT3 has a dual role: dominant-negative missense mutations in the SH2 domain cause hyper-IgE syndrome (germline), while gain-of-function missense mutations drive somatic malignancies. The gene-level benign missense constraint metrics were not evaluated. This criterion requires a dedicated Z-score/missense constraint analysis not available in the evidence packet.
PP3	Not met	PP3 requires multiple lines of computational evidence supporting a deleterious effect. REVEL score is 0.359 (below commonly used thresholds of ≥0.5–0.75 for pathogenic prediction), BayesDel is −0.126 (benign-leaning), and SpliceAI shows no splice impact (max delta = 0.00). In silico predictors do not reach consensus supporting a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	PP4 requires that the patient's phenotype or family history is highly specific for the disease associated with the gene. No patient phenotype information was available in the case evidence packet.
PP5	Not met	PP5 requires a reputable source (e.g., clinical laboratory with expert review) to have classified the variant as pathogenic. ClinVar shows conflicting interpretations: two submitters classify as Uncertain Significance (LabCorp, SCV001737716; Labcorp Genetics, SCV004589843) and one as Pathogenic (CeGaT, SCV001371123). None are from an expert panel. The conflicting classifications, with the majority reporting VUS, preclude PP5 application.	clinvar
BA1	Not met	BA1 requires an allele frequency >1% in a general population database. The variant is absent in gnomAD v2.1 and extremely rare in gnomAD v4.1 (AF=1.24×10⁻⁶; 2/1,614,212 alleles), far below the 1% threshold.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 requires an allele frequency >0.3% in a general population database. The variant is absent in gnomAD v2.1 and extremely rare in gnomAD v4.1 (AF=1.24×10⁻⁶), far below the 0.3% threshold.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires observation of the variant in a healthy adult individual for a fully penetrant disorder. The two alleles observed in gnomAD v4.1 are from exome data of individuals with unknown phenotype and cannot be confirmed as healthy adult carriers. No other healthy adult observation is documented.	gnomad_v4
BS3	Not met	BS3 requires well-established in vitro/in vivo functional studies showing no damaging effect on the gene product. Available evidence suggests the opposite: OncoKB annotates this variant as 'Likely Oncogenic' (gain-of-function), and published functional studies of STAT3 SH2 domain mutations (PMID:22859607) describe altered STAT3 activation and gene deregulation. No evidence of normal function for N647I was identified. BS3 is not met.	oncokb PMID:22859607
BS4	Not met	BS4 requires lack of segregation of the variant with disease in affected family members. No published pedigree with non-segregation data was identified for NM_139276.2:c.1940A>T.
BP1	Not met	BP1 applies to a missense variant in a gene where truncating variants are the primary mechanism of disease. STAT3-related hyper-IgE syndrome (autosomal dominant) is caused by dominant-negative missense mutations in the SH2 and DNA-binding domains, not by truncating/haploinsufficiency variants. The primary disease mechanism for STAT3 germline disorders involves missense variants, so BP1 does not apply.
BP2	Not met	BP2 requires observation of the variant in trans with a known pathogenic variant in a gene for a fully penetrant dominant disorder. No individual carrying NM_139276.2:c.1940A>T in trans with a known pathogenic STAT3 variant has been reported.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on the gene product. REVEL score is 0.359 (indeterminate), BayesDel is −0.126 (benign-leaning but not strongly so), and SpliceAI delta is 0.00. While BayesDel is slightly negative and SpliceAI shows no splice effect, REVEL does not strongly support benign impact and a consensus of benign prediction across tools is absent.	revel bayesdel spliceai
BP5	Not assessed	BP5 requires an alternate molecular basis for disease in a case where the variant was observed. No case with an alternate molecular cause was identified in the available evidence.
BP6	Not met	BP6 requires a reputable source to classify the variant as benign. ClinVar shows two submissions as Uncertain Significance and one as Pathogenic; no submitter has classified the variant as Benign or Likely Benign.	clinvar
BP7	N/A	BP7 applies only to synonymous (silent) variants without predicted splice impact. NM_139276.2:c.1940A>T is a missense variant (p.Asn647Ile) and is not synonymous.	spliceai

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