Variant classification summary

NM_139276.3:c.1919A>T

STAT3 · NP_644805.1:p.(Tyr640Phe) · NM_139276.3

GRCh37: chr17:40474482 T>A · GRCh38: chr17:42322464 T>A

Gene: STAT3 Transcript: NM_139276.3

Final call

Likely Pathogenic

PS3 strong PM2 supporting PP3 supporting

Variant details

Gene

STAT3

Transcript

NM_139276.3

Protein

NP_644805.1:p.(Tyr640Phe)

gnomAD AF

1.8586946016073992e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS3 strong is met by concordant activating functional evidence for Y640F.

2

Likely Pathogenic: PM2 supporting is met because the variant is extremely rare in gnomAD with no homozygotes.

3

Likely Pathogenic: PP3 supporting is met because REVEL is 0.644.

Final determination: Under the generic ACMG/AMP 2015 fallback, 1 strong pathogenic criterion plus at least 2 supporting pathogenic criteria leads to Likely Pathogenic.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: Y640F is documented, but no different nucleotide change producing the same amino-acid change is identified as previously pathogenic.	clinvar
PS2	Not assessed	Not assessed: confirmed maternity, paternity, disease phenotype, and absence of family history are not documented for STAT3 c.1919A>T.	clinvar
PS3	Met	Met, strong: orthogonal assays showed increased STAT3 transcriptional activity and phosphorylation, while Y640F-expressing cells formed colonies and metastasized in mice.	PMID:22591296 PMID:25873174 PMID:25586472
PS4	Not assessed	Not assessed: affected-cohort observations lack a matched control comparison, so the required OR >5.0 and 95% confidence-interval exclusion of 1.0 cannot be calculated.	PMID:22591296 PMID:22859607 PMID:23926297 gnomad_v4
PM1	Not assessed	Not assessed: Y640F is in the recurrent SH2-domain hotspot, but no comprehensive evidence establishes absence of benign variation in that region.	PMID:22591296 PMID:25873174 PMID:22859607 gnomad_v4
PM2	Met	Met at supporting strength: gnomAD v4.1 AF is 1.85869e-06 (3/1,614,036 alleles), below the <=0.0001 PM2 threshold, with no homozygotes.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: reports describe somatic Y640F, with no documented germline pathogenic variant in trans or parent/offspring phase testing.	PMID:22591296 PMID:22859607 PMID:23926297 clinvar
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense change at STAT3 residue 640 is identified as previously established pathogenic.	PMID:22591296 PMID:25873174 PMID:22859607 pm5_candidates
PM6	Not assessed	Not assessed: no affected proband with assumed de novo STAT3 c.1919A>T is documented, and the available de novo report concerns p.K290N.	clinvar
PP1	Not assessed	Not assessed: no multiple affected family members, informative meioses, or familial genotype-phenotype cosegregation are reported for this variant.	clinvar PMID:22591296 PMID:22859607 PMID:23926297
PP2	Not assessed	Not assessed: evidence does not establish both low benign missense variation and a common missense disease mechanism for STAT3.	PMID:22591296 PMID:25873174 gnomad_v4
PP3	Met	Met at supporting strength: missense REVEL score 0.644 meets the generic PP3 threshold of >=0.644.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family-history description is available to determine whether the presentation is highly specific for a single-etiology disease.
PP5	Not met	Not met: the exact ClinVar variant has zero expert-panel submissions, so non-expert Pathogenic assertions cannot trigger PP5.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 6.8e-07, below the >=0.05 BA1 threshold, with conflicting ClinVar classifications.	gnomad_v4 gnomad_v2 clinvar
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 6.8e-07, far below the generic >=0.01 BS1 threshold in a population with 1,179,992 alleles.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: gnomAD reports 3 heterozygous alleles and 0 homozygotes but does not establish healthy-adult status, genotype applicability, or early full penetrance.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: reviewed studies showed activating STAT3 effects, but no well-established assay demonstrated no damaging effect on protein function or splicing.	PMID:22591296 PMID:25873174 PMID:25586472
BS4	Not assessed	Not assessed: no informative affected family members are documented with a negative genotype for STAT3 c.1919A>T.	clinvar PMID:22591296 PMID:22859607 PMID:23926297
BP1	Not met	Not met: available STAT3 disease evidence centers on recurrent activating missense variants, not a primarily truncating disease mechanism.	PMID:22591296 PMID:25873174 PMID:25586472 clinvar
BP2	Not assessed	Not assessed: no germline cis/trans observation with a pathogenic variant is documented; available Y640F reports are somatic.	PMID:22591296 PMID:22859607 PMID:23926297 clinvar
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL score 0.644 exceeds the generic BP4 supporting threshold of <=0.29.	revel
BP5	Not assessed	Not assessed: no individual case documents an alternate molecular diagnosis that explains the disease independently of this variant.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present; the record has zero expert-panel submissions.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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