STAT3

Final classification

VUS

STAT3 c.1940A>T · p.Asn647Ile

STAT3

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.

Gene

STAT3

Transcript

NM_139276.2

HGVS · transcript:coding

NM_139276.2:c.1940A>T

Consequence

N/A

GRCh38

chr17:42322443 T>A

GRCh37

chr17:40474461 T>A

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 supporting; combination = 1 moderate + 1 supporting, which maps to VUS. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 supporting; combination = 1 moderate + 1 supporting, which maps to VUS.

Classification rationale

PM1PM2 VUS

STAT3 c.1940A>T

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 STAT3.¹ 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.² 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.³ 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.⁴ 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.⁵ 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.⁶

PM1 + PM2 → VUS

1 generic_acmg_combination_rules

2 PMID:22859607 ↗

3 gnomad_v2 ↗gnomad_v4 ↗

4 revelbayesdelspliceai ↗

5 clinvar ↗

6 generic_acmg_combination_rules

Gene diagram · NM_139276.2 · variants mapped to exon structure

STAT3 NM_139276.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 20 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM1 moderate Pathogenic

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.

UniProt SH2 domain annotation: residues 583–688. PMID:22859607 reports SH2 domain (exons 20-21) as site of recurrent mutations. Position N647 within SH2 domain confirmed.

oncokb ↗PMID:22859607 ↗

✓

PM2 supporting Pathogenic

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 v2.1: 0/251490 (0.0%). gnomAD v4.1: 2/1614

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PS1 PS1 requires a different nucleotide change at the same codon leading to the same missense change (N647I) that has been previously classified as pathogenic.

PS2 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.

PS3 Well-established in vitro/in vivo functional studies are required for PS3.

PS4 PS4 requires that prevalence of the variant in affected individuals is significantly increased compared to controls.

PM6 PM6 requires a de novo observation without confirmation of both maternity and paternity.

PP1 PP1 requires cosegregation of the variant with disease in multiple affected family members.

PP2 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.

PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect.

PP4 PP4 requires that the patient's phenotype or family history is highly specific for the disease associated with the gene.

PP5 PP5 requires a reputable source (e.g., clinical laboratory with expert review) to have classified the variant as pathogenic.

Benign

BA1 BA1 requires an allele frequency >1% in a general population database.

BS1 BS1 requires an allele frequency >0.3% in a general population database.

BS2 BS2 requires observation of the variant in a healthy adult individual for a fully penetrant disorder.

BS3 BS3 requires well-established in vitro/in vivo functional studies showing no damaging effect on the gene product.

BS4 BS4 requires lack of segregation of the variant with disease in affected family members.

BP1 BP1 applies to a missense variant in a gene where truncating variants are the primary mechanism of disease.

BP2 BP2 requires observation of the variant in trans with a known pathogenic variant in a gene for a fully penetrant dominant disorder.

BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene product.

BP5 BP5 requires an alternate molecular basis for disease in a case where the variant was observed.

BP6 BP6 requires a reputable source to classify the variant as benign.

N/A · 3 PVS1 · PM5 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.23899e-06; MAF= 0.00012%, 2/1614212 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69488e-06; MAF= 0.00017%, 2/1180028 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251490 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16256 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00012% · 2 / 1,614,212
0 hom · FAF 2.8e-05%

European (non-Finnish)

2 / 1,180,028

0.00017%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / 251,490
0 hom

Not observed in any ancestry group.

+ 8 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Pathogenic (1 clinical laboratory). (ClinVarID = 932423)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.359. BayesDel score = -0.125529.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52882818, n = 28 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

3papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 5 further PMIDs triaged but not cited — see Sources & References.

STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia.

PMID 22859607 ↗ · Jerez A et al. · 2012 Oct 11 CLINVAR · functional

Found

reports SH2 domain (exons 20-21) as site of recurrent mutations.

Applied to

→PM1 supports · met

Distinct mutations at the same positions of STAT3 cause either loss or gain of function.

PMID 27345172 ↗ · Chandrasekaran P et al. · 2016 Oct ONCOKB · functional

Found

Structured finding pending for this record — see source link.

Applied to

→PM1 supports · met

Structural Implications of STAT3 and STAT5 SH2 Domain Mutations.

PMID 31717342 ↗ · de Araujo ED et al. · 2019 Nov 8 CLINVAR · functional

Found

Structured finding pending for this record — see source link.

Applied to

→PM1 supports · met

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 5 PMIDs not cited in assessment

31002364 ↗ JAK3/STAT3 oncogenic pathway and PRDM1 expression stratify clinicopathologic features of extranodal NK/T‑cell lymphoma, nasal type. CLINVAR

31278738 ↗ Molecular Genetics in the Diagnosis and Biology of Lymphoid Neoplasms. CLINVAR

32273478 ↗ Genetic lesions in MYC and STAT3 drive oncogenic transcription factor overexpression in plasmablastic lymphoma. CLINVAR

33579790 ↗ Oncogenetic landscape of lymphomagenesis in coeliac disease. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

Re-run this variant?