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 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

Population frequency

Overall AF

2 / 1,614,212

0.00012%

Highest · European (non-Finnish)

0.00017%

Homozygotes

grpmax FAF

2.8e-05%

Allele frequency by ancestry — gnomAD v4.1

observed in 1 of 9 groups

Ancestry	Allele count	Frequency	Homozygotes
European (non-Finnish)	2 / 1,180,028	0.00017%	0
Admixed American	0 / 60,024	—	—
European (Finnish)	0 / 64,044	—	—
Amish	0 / 912	—	—
East Asian	0 / 44,890	—	—
Middle Eastern	0 / 6,062	—	—
South Asian	0 / 91,086	—	—
Ashkenazi Jewish	0 / 29,602	—	—
African/African American	0 / 75,056	—	—

“

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.

Overall AF

Not observed

Homozygotes

Not observed in any ancestry group across 8 populations in gnomAD 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).

“

Absent from gnomAD-Canada v1.0.

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 · 12 PMIDs triaged · 8 high-priority

12papers screened

Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.

27345172 ↗ functional

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

BS3PM1PS3

22859607 ↗ functional

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

Chronic lymphoproliferative disorders of natural killer cells (CLPD-NKs) and T-cell large granular lymphocytic leukemias (T-LGLs) are clonal lymphoproliferations arising from either natural killer cells or cytotoxic T lymphocytes (CTLs). We have investigated for distribution and functional significance of mutations in 50 CLPD-NKs and 120 T-LGL patients by direct sequencing, allele-specific PCR, an

BS3PP5PS3PS4

27345172 ↗ case observation

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

PP5PS4

31002364 ↗ splicing rna

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

The inactivation of tumor suppressor gene positive regulatory domain containing I (PRDM1) and activation of signal transducer and activator of transcription 3 (STAT3) have been detected in the majority of extranodal NK/T‑cell lymphoma, nasal type (EN‑NK/T‑NT) cases. In the present study, their association with and effects on the clinicopathologic features of EN‑NK/T&#x2

BP7PP3PP5PS4PVS1

31278738 ↗ splicing rna

Molecular Genetics in the Diagnosis and Biology of Lymphoid Neoplasms.

The 2017 Workshop of the Society for Hematopathology/European Association for Haematopathology reviewed the role of molecular genetics in the diagnosis and biology of lymphoid neoplasms. The Workshop Panel reviewed 82 cases. Molecular genetic testing reveals alterations that expand the spectrum of diseases such as DUSP22 rearrangement in ALK-negative anaplastic large cell lymphoma, large B-cell ly

BP7PP3PP5PS4PVS1

31717342 ↗ functional

Structural Implications of STAT3 and STAT5 SH2 Domain Mutations.

Src Homology 2 (SH2) domains arose within metazoan signaling pathways and are involved in protein regulation of multiple pleiotropic cascades. In signal transducer and activator of transcription (STAT) proteins, SH2 domain interactions are critical for molecular activation and nuclear accumulation of phosphorylated STAT dimers to drive transcription. Sequencing analysis of patient samples has reve

BS3PP5PS3PS4

32273478 ↗ splicing rna

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

Plasmablastic lymphoma mutational profile is undescribed. Here we performed a targeted exonic NGS analysis of 30 plasmablastic lymphoma cases with a B cell lymphoma dedicated panel and FISH for the detection of MYC rearrangements. A complete phenotyping of the neoplastic and microenvironment cell populations was also performed. We have identified an enrichment in recurrent genetic events in MYC (6

BP7PP3PP5PS4PVS1

33579790 ↗ functional

Oncogenetic landscape of lymphomagenesis in coeliac disease.

Enteropathy-associated T-cell lymphoma (EATL) is a rare but severe complication of coeliac disease (CeD), often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCDII). Knowledge on underlying oncogenic mechanisms remains scarce. Here, we analysed and compared the mutational landscape of RCDII and EATL in order to identify genetic drivers of

BS3PP5PS3PS4

28492532 ↗ background review

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

PP5PS4

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots