STAT3 c.1919A>T, p.Tyr640Phe

Reasoning

PS3 is met at strong strength. Multiple independent, variant-specific studies evaluate STAT3 p.Tyr640Phe (NM_139276.3:c.1919A>T) using orthogonal functional approaches. Koskela et al. (PMID:22591296) reported markedly increased STAT3 transcriptional activity in a luciferase reporter assay under basal and IL-6-stimulated conditions and nuclear phosphorylated STAT3 in Y640F patient samples. Crescenzo et al. (PMID:25873174) demonstrated constitutive Tyr705 phosphorylation, STAT3 reporter activation, increased colony formation, and lung metastases in NSG mice for Y640F-expressing cells. These results are biologically relevant to STAT3 signaling and are concordant with a gain-of-function effect. The evidence is not described as validated and reproducible in a clinical diagnostic laboratory, but the combination of orthogonal cellular assays and an in vivo model is well-established functional evidence supportive of a damaging effect on the gene product.

Rule

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

Evidence considered

• Koskela et al. 2012 (PMID:22591296): in a 77-patient T-LGL cohort, Y640F was evaluated by luciferase reporter assay, bone-marrow immunohistochemistry, and nuclear-extract Western blotting; Y640F showed markedly increased transcriptional activity under basal and IL-6-stimulated conditions, and patient samples showed nuclear phosphorylated STAT3.
• Crescenzo et al. 2015 (PMID:25873174): STAT3-null mouse embryonic fibroblasts expressing Y640F showed high Tyr705 phosphorylation, STAT3-driven luciferase activation, increased colony formation, and lung metastases after injection into NSG mice.
• Kobayashi et al. 2015 (PMID:25586472): Y640F was validated by Sanger sequencing and associated with increased STAT3 Tyr705 phosphorylation; STAT3 knockdown reduced the proportion of Y640F-mutant cells in cell-growth/selection experiments.

Sources

Reasoning

PM2 is met at supporting strength under the supplied generic SVI threshold. The variant is present at an extremely low frequency in gnomAD v4.1 (3/1,614,036 alleles; AF 1.85869e-06; no homozygotes), with gnomAD v4.1 grpmax FAF=6.8e-07, which is below the <=0.0001 PM2 supporting threshold. gnomAD v2.1 independently shows only 1/251,474 exome alleles (AF 3.97655e-06) and no homozygotes. No governing VCEP or non-cancer/exome-only override is present, so the all-comers gnomAD entries are the applicable defaults.

Rule

PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868) ... Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.

Evidence considered

• gnomAD v4.1 evidence: AF 1.85869e-06 (3/1,614,036 combined alleles), no homozygotes, and grpmax FAF=6.8e-07; European (non-Finnish) AF was 2.54239e-06 (3/1,179,992 alleles).
• gnomAD v2.1 evidence: AF 3.97655e-06 (1/251,474 exome alleles), no homozygotes; European (non-Finnish) AF was 8.7909e-06 (1/113,754 alleles).
• The generic PM2 calibration supplied for this case is <=0.0001 for supporting strength, identified as the ClinGen SVI recommendation to downgrade PM2 to Supporting (ACMG/AMP 2015 source PMID:25741868).
• No CSPEC/VCEP was found for STAT3, and no governing non-cancer or exome-only population-source specification was provided; therefore the all-comers gnomAD v2.1 and v4.1 entries are used.

Sources

Reasoning

The variant is a missense substitution, NM_139276.3:c.1919A>T, p.(Tyr640Phe), so the governing computational path is REVEL only; SpliceAI is not used for PP3/BP4 in this situation. REVEL is 0.644, meeting the generic ClinGen SVI supporting PP3 threshold of >= 0.644 from Pejaver et al. 2022 (PMID:36413997). BayesDel is not used because no generic ACMG-strength calibration is established. The criterion is therefore met at supporting strength.

Rule

PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)

Evidence considered

• NM_139276.3:c.1919A>T is a missense variant producing NP_644805.1:p.(Tyr640Phe); the missense path uses REVEL only.
• Local REVEL lookup reports 0.644 for this variant.
• Pejaver et al. 2022, ClinGen SVI REVEL calibration, PMID:36413997: generic PP3 supporting threshold is >= 0.644.
• SpliceAI max delta 0.004 was not used because splice prediction is not the governing path for a missense variant; BayesDel was not used because no generic ACMG-strength calibration is established.

Sources

Reasoning

The governing rule is ACMG/AMP 2015: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." Under the required generic application, PP5 is restricted to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification. ClinVar identifies the exact NM_139276.3:c.1919A>T (p.Tyr640Phe) variant, but the submission audit reports zero expert-panel submissions; available Pathogenic assertions are clinical-laboratory or other non-expert submissions and the aggregate record is conflicting. Therefore the PP5 trigger is absent.

Rule

Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.

Evidence considered

• ClinVar exact-variant record for NM_139276.3:c.1919A>T (p.Tyr640Phe) is conflicting and reports zero expert-panel submissions; Pathogenic assertions are from non-expert clinical or research submissions.

Sources

Reasoning

BA1 is not met. The required filtering frequency is the gnomAD v4.1 grpmax FAF of 6.8e-07, far below the generic stand-alone threshold of >=0.05; the highest observed point estimate, 2.54239e-06 in 1,179,992 European (non-Finnish) alleles, also remains below threshold. gnomAD v2.1 showed 1/251,474 alleles (AF 3.97655e-06) with no homozygotes. In addition, ClinVar contains conflicting Pathogenic and Uncertain significance submissions, so the default frequency does not justify a stand-alone benign conclusion.

Rule

BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868) ... Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.

Evidence considered

• gnomAD v4.1 evidence: combined AF 1.85869e-06 (3/1,614,036 alleles), no homozygotes, and grpmax FAF=6.8e-07; the highest observed population point estimate was 2.54239e-06 in European (non-Finnish) individuals (3/1,179,992 alleles).
• gnomAD v2.1 evidence: AF 3.97655e-06 (1/251,474 exome alleles), no homozygotes; European (non-Finnish) AF 8.7909e-06 (1/113,754 alleles).
• The generic BA1 calibration supplied for this case is >=0.05, identified as the ACMG/AMP 2015 stand-alone benign allele-frequency threshold (PMID:25741868).
• ClinVar case summary: Pathogenic submissions from 4 clinical laboratories and Uncertain significance submissions from 3 clinical laboratories, with no expert-panel submission and conflicting classifications.

Sources

Reasoning

BS1 is not met on the available population data. The appropriate filtering frequency is gnomAD v4.1 grpmax FAF=6.8e-07, below the generic BS1 default threshold of >=0.01; the highest observed point estimate is only 2.54239e-06 in a population with 1,179,992 observed alleles, well above the 2,000-allele minimum. The variant is associated with a conflicting ClinVar record rather than a benign consensus, but no maximum-credible-frequency calculation is needed because the filtering FAF is already far below the default threshold.

Rule

BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168) ... Allele frequency is greater than expected for the disorder.

Evidence considered

• gnomAD v4.1 evidence: grpmax FAF=6.8e-07; highest observed population point estimate was 2.54239e-06 in European (non-Finnish) individuals, based on 3/1,179,992 alleles, with no homozygotes.
• gnomAD v2.1 evidence: combined AF 3.97655e-06 from 1/251,474 exome alleles and highest observed European (non-Finnish) AF 8.7909e-06 from 1/113,754 alleles, with no homozygotes.
• The generic BS1 calibration supplied for this case is >=0.01; it is identified as the generic ClinGen SVI default, with per-gene derivation preferred under Whiffin et al. 2017 (PMID:28518168).
• The gnomAD v4.1 frequency used for BS1 is the filtering grpmax FAF rather than the population point estimate, and the relevant population has more than 2,000 observed alleles.

Sources

Reasoning

The available gene-level evidence does not support a STAT3 disease pattern in which primarily truncating variants are known to cause disease. Instead, the reviewed disease-associated evidence centers on recurrent activating missense substitutions, including Y640F, in the STAT3 SH2 domain. The BP1 pattern is therefore not supported for this variant.

Rule

Missense variant in a gene for which primarily truncating variants are known to cause disease.

Evidence considered

• Koskela et al., Crescenzo et al., and Huang et al. report recurrent activating STAT3 missense changes, including Y640F, in the SH2 domain and associated disease contexts.
• ClinVar lists the variant in STAT3 gain-of-function and immune/hematologic disease contexts, with pathogenic submissions for the missense variant, although ClinVar classifications were not used alone as the criterion decision.

Still missing

• A comprehensive disease-variant spectrum review distinguishing the proportion of truncating versus missense STAT3 disease variants is not available.

Sources

Reasoning

The variant is a missense substitution, so BP4 must be assessed through the REVEL path only; the SpliceAI result cannot substitute for an indeterminate or non-supportive missense prediction. REVEL is 0.644, which is not <= 0.29, the generic ClinGen SVI supporting BP4 threshold from Pejaver et al. 2022 (PMID:36413997), and therefore does not support a benign computational prediction. BayesDel is not used because no generic ACMG-strength calibration is established. BP4 is not met.

Rule

BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)

Evidence considered

• NM_139276.3:c.1919A>T is a missense variant; BP4 uses the REVEL path only.
• Local REVEL lookup reports 0.644 for this variant.
• Pejaver et al. 2022, ClinGen SVI REVEL calibration, PMID:36413997: generic BP4 supporting threshold is <= 0.29.
• SpliceAI max delta 0.004 was not used because splice prediction cannot provide BP4 support for a missense variant; BayesDel was not used because no generic ACMG-strength calibration is established.

Sources

Reasoning

The governing rule is ACMG/AMP 2015: "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation." Under the required generic application, BP6 is restricted to an exact-variant ClinVar expert-panel Benign or Likely benign classification. ClinVar identifies the exact variant but the submission audit reports zero expert-panel submissions and no expert-panel Benign/Likely benign classification; the available record is conflicting. Therefore BP6 is not met.

Rule

Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.

Evidence considered

• ClinVar exact-variant submission audit reports zero expert-panel submissions and no expert-panel Benign or Likely benign classification; the aggregate record is conflicting.

Sources

Reasoning

The variant is STAT3 p.Tyr640Phe (Y640F), but the available evidence documents this same nucleotide/protein change and does not identify a previously established pathogenic variant producing p.Tyr640Phe through a different nucleotide change. The PS1 comparator requirement therefore cannot be evaluated from the available evidence.

Rule

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

Evidence considered

• ClinVar identifies the queried variant as NM_139276.3(STAT3):c.1919A>T (p.Tyr640Phe), with conflicting submissions rather than a separate nucleotide change causing the same amino-acid substitution.

Still missing

• A validated pathogenic alternate nucleotide change producing STAT3 p.Tyr640Phe at codon 640 is not identified.

Sources

Reasoning

The available evidence does not document a proband with the disease carrying STAT3 c.1919A>T together with confirmed maternity and paternity, nor does it establish absence of family history. The de novo report cited in the literature concerns STAT3 c.870A>T (p.K290N), not this variant. Therefore PS2 cannot be assessed.

Rule

PS2

Evidence considered

• ClinVar exact-variant submissions for NM_139276.3(STAT3):c.1919A>T (p.Tyr640Phe) do not provide documented maternity and paternity confirmation, a disease-specific proband phenotype, or family-history information.
• The cited publication titled 'A novel de novo activating mutation in STAT3 identified in a patient with common variable immunodeficiency (CVID)' reports STAT3 c.870A>T (p.K290N), not the reviewed c.1919A>T (p.Y640F), so it cannot establish PS2 for this variant.

Still missing

• A disease-affected proband carrying STAT3 c.1919A>T must be documented.
• Parental testing confirming both maternity and paternity is not available.
• Family history information is not available.
• The cited de novo publication concerns a different STAT3 variant, c.870A>T (p.K290N).

Sources

Reasoning

The governing rule is ACMG/AMP 2015: "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls." The specified note requires a case-control RR or OR >5.0 with a 95% confidence interval that does not include 1.0. The literature-pass PS4 index was checked: PMID:22591296 reports Y640F in 13/77 T-LGL patients but provides no unaffected or population control cohort; PMID:22859607 reports a somatic Y640F-containing disease cohort without an unaffected control comparison; PMID:23926297 reports Y640F in 2 aplastic-anemia samples within a 367-MDS/140-AA cohort, not a matched control group; PMID:30940614 describes a pediatric Evans syndrome case cohort including STAT3 among several genes but does not identify this exact variant in the abstract or provide an unaffected control comparison; PMID:20301786 has no retrievable title or abstract in the case materials; PMID:22918138 is a general diagnostic-genome-sequencing report, not a variant-specific case-control study; and PMID:34131312 is an ACMG chromosomal-microarray technical standard, not a variant-specific case-control study. The variant is present in gnomAD v4.1 at 3/1,614,036 alleles (AF 1.85869e-06), but the available affected observations are somatic disease cohorts and no matched-ancestry germline case-control design is established, so a valid OR and 95% CI for PS4 cannot be calculated from the supplied evidence. The required numeric test is therefore unavailable: OR > 5.0 and 95% CI excluding 1.0 cannot be evaluated.

Rule

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.

Evidence considered

• PMID:22591296: full text reports "Y640F mutations were detected in 17% of patients (13 of 77)" in a T-cell large granular lymphocytic leukemia cohort, with no unaffected control cohort reported.
• PMID:22859607: full text reports Y640F among somatic STAT3 mutations in a 170-patient CLPD-NK/T-LGL disease cohort, without a matched unaffected control comparison.
• PMID:23926297: full text reports Y640F in confirmed aplastic-anemia samples UPN1 and UPN3, within cohorts of 367 MDS and 140 idiopathic AA patients; these are affected cohorts, not unaffected controls.
• PMID:30940614: available abstract reports 80 tested pediatric Evans syndrome patients and 32 patients with pathogenic mutations across nine immune-deficiency genes including STAT3, but does not name this exact Y640F variant and does not provide an unaffected control comparison.
• PMID:20301786: listed in literature_pass.json as a PS4 candidate, but no title, abstract, or full text is available in the case materials for verification.
• PMID:22918138: available abstract is a general Association for Molecular Pathology report on clinical diagnostic genome sequencing and does not report variant-specific case-control data.
• PMID:34131312: available abstract is an ACMG chromosomal-microarray technical standard and does not report variant-specific case-control data.
• gnomAD v4.1: 3/1,614,036 alleles, AF 1.85869e-06; this population frequency alone is not a matched-ancestry case-control comparison for the somatic disease observations.

Still missing

• A variant-specific affected-versus-unaffected or matched-ancestry population control study with counts is needed to calculate OR/RR and its 95% CI.
• The full text or reliable abstract for PMID:20301786 is unavailable in the case materials.

Sources

Reasoning

STAT3 p.Tyr640Phe lies in the SH2 domain and is reported as a recurrent hotspot substitution in that domain. However, the generic PM1 definition also requires the hotspot or critical domain to be without benign variation, and the available evidence does not provide a sufficiently comprehensive assessment of benign variation across the relevant SH2 region. The domain/hotspot component is supported, but the complete generic criterion cannot be concluded.

Rule

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

Evidence considered

• Koskela et al. report Y640F in 13 of 77 T-cell large granular lymphocytic leukemia patients and place it in the STAT3 SH2-domain dimerization interface; the paper states, "Y640F mutations were detected in 17% of patients (13 of 77)".
• Crescenzo et al. describe Y640F as a recurrent missense substitution in a STAT3 SH2-domain hotspot, together with N647I, D661Y, and A662V.
• Jerez et al. report that Y640F and D661Y accounted for 80% of the somatic STAT3 variations identified, supporting recurrence at the residue/domain level.
• gnomAD v4.1 reports the queried Y640F allele at AF 1.85869e-06, but this single-variant frequency does not establish the absence of benign variation throughout the SH2 domain.

Still missing

• A validated assessment of benign variation across the relevant STAT3 SH2 hotspot/critical domain is unavailable.

Sources

Reasoning

The queried STAT3 p.Tyr640Phe variant is reported in the reviewed literature as a somatic mutation in affected cancer or bone-marrow-failure cohorts, including one report of uniparental-disomy-associated homozygosity, but no germline affected-proband observation with a pathogenic allele in trans is documented. Parent or offspring testing establishing phase is also absent. Therefore the recessive PM3 requirement cannot be assessed from the available evidence.

Rule

For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.

Evidence considered

• The reviewed reports identify Y640F as a somatic STAT3 mutation: 13/77 T-cell large granular lymphocytic leukemia patients in PMID:22591296, recurrent somatic mutations in PMID:22859607, and low-level somatic T-cell clones in PMID:23926297.
• PMID:22591296 reports one Y640F case with uniparental disomy of 17q and homozygosity, not a confirmed germline compound-heterozygous or trans configuration with a pathogenic variant.
• The ClinVar record includes germline submissions but does not provide affected-proband allelic phase, a pathogenic variant in trans, or parent/offspring testing for this variant.

Still missing

• A germline affected-proband observation with a confirmed pathogenic variant in trans is not documented.
• Parent or offspring testing establishing phase is not available.
• The relevant STAT3 disorder's recessive inheritance context is not established for this observation.

Sources

Reasoning

The available literature reports STAT3 p.Tyr640Phe and other recurrent STAT3 substitutions at different residues, but it does not identify a different missense substitution at residue 640 that has been established as pathogenic. The required same-residue pathogenic comparator is therefore unavailable.

Rule

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

Evidence considered

• The reviewed STAT3 studies report Y640F itself and different-residue substitutions including N647I, D661Y, and A662V; they do not provide a different pathogenic missense substitution at residue 640.
• The PM5 candidate record contains zero harvested same-residue candidates and explicitly does not establish classic same-residue PM5 semantics.

Still missing

• A validated pathogenic missense comparator at STAT3 residue 640 is not identified.

Sources

Reasoning

No reliable case-level evidence shows that STAT3 c.1919A>T arose de novo in an affected patient. The only identified de novo publication concerns the different variant c.870A>T (p.K290N), and no parental testing or applicable proband report is available for c.1919A>T. Therefore PM6 cannot be assessed.

Rule

PM6

Evidence considered

• ClinVar exact-variant evidence does not document assumed de novo occurrence of STAT3 c.1919A>T in an affected patient.
• The publication cited for de novo STAT3 disease reports c.870A>T (p.K290N), not c.1919A>T (p.Y640F), and therefore is not usable for PM6 for this variant.

Still missing

• A case report or cohort record for the reviewed variant in an affected patient is not available.
• Evidence that the reviewed variant was de novo is not available.
• Parental testing information is not available, even at the level required to support assumed de novo status.

Sources

Reasoning

No affected family members carrying STAT3 c.1919A>T, informative meioses, or genotype-phenotype cosegregation are reported. The available variant-specific literature describes somatic disease cohorts rather than familial germline segregation. Therefore PP1 cannot be assessed.

Rule

PP1

Evidence considered

• ClinVar exact-variant submissions do not report familial segregation for STAT3 c.1919A>T.
• PMID:22591296 reports Y640F in a somatic T-cell large granular lymphocytic leukemia cohort, including 13 of 77 patients, but provides no familial cosegregation data.
• PMID:22859607 reports Y640F among somatic STAT3 mutations in chronic lymphoproliferative disorders and provides no affected-family segregation analysis.
• PMID:23926297 reports somatic Y640F-mutated T-cell clones in aplastic anemia and myelodysplastic syndrome cohorts, not familial germline segregation.

Still missing

• Family pedigree and affected-relative information are not available.
• Genotypes and phenotypes of affected relatives are not available.
• No informative meioses or cosegregation data are available.

Sources

Reasoning

The available evidence supports recurrent activating STAT3 missense changes in somatic disease, but it does not establish both components required for PP2: a low rate of benign missense variation for STAT3 and missense variants as a common disease mechanism under the generic germline criterion.

Rule

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

Evidence considered

• The literature reports recurrent activating STAT3 missense substitutions, including Y640F, in somatic hematologic malignancies, but recurrence in selected tumors is not a validated PP2 gene-level threshold.
• gnomAD v4.1 provides the queried variant's population frequency but not a gene-level benign missense constraint assessment sufficient for PP2.

Still missing

• No validated gene-level benign missense constraint or equivalent low-benign-missense metric is provided.
• No sufficiently comprehensive generic disease-mechanism assessment establishes missense variants as a common STAT3 disease mechanism for PP2.

Sources

Reasoning

The governing rule is ACMG/AMP 2015: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The case materials do not provide a patient phenotype, family history, or a single-etiology disease diagnosis for this variant, so phenotype specificity cannot be judged.

Rule

Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.

Still missing

• Patient-level phenotype, family history, and the specific suspected disease diagnosis are required.

Reasoning

BS2 cannot be assessed from the available evidence. gnomAD v4.1 reports three heterozygous alleles and no homozygotes, but the population record does not identify an individual as a healthy adult, establish the relevant STAT3 disease inheritance and expected full penetrance at an early age, or provide phenotype follow-up. Therefore, the presence of control alleles cannot be converted into the required observation of a healthy adult individual with the applicable genotype.

Rule

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.

Evidence considered

• gnomAD v4.1 evidence: 3/1,614,036 total alleles, no homozygotes; the database frequency record does not provide individual-level age, health, genotype, or phenotype information.
• gnomAD v2.1 evidence: 1/251,474 exome alleles, no homozygotes; the database frequency record likewise does not establish a healthy adult observation for BS2.

Still missing

• An identified healthy adult individual with the applicable disease genotype.
• Confirmed STAT3 disease inheritance, age-related penetrance, and phenotype information for that individual.

Sources

Reasoning

BS3 is not assessed because the reviewed variant-specific functional studies evaluated activating or damaging effects of STAT3 p.Tyr640Phe and did not provide well-established evidence showing no damaging effect on protein function or splicing. The available assays therefore cannot support the benign functional criterion.

Rule

Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.

Evidence considered

• The reviewed variant-specific studies tested STAT3 p.Tyr640Phe for increased signaling, transcriptional activity, phosphorylation, cellular growth, or tumor formation; none reported a benign functional or splicing result suitable for BS3.

Still missing

• No well-established variant-specific functional or splicing study demonstrating absence of a damaging effect was identified.

Sources

Reasoning

No family containing affected members with informative testing is documented, and no affected relative is shown to lack STAT3 c.1919A>T. The available somatic cohort reports do not provide familial non-segregation evidence or permit evaluation of phenocopies and alternative pathogenic variants. Therefore BS4 cannot be assessed.

Rule

BS4

Evidence considered

• ClinVar exact-variant submissions do not document affected relatives who test negative for STAT3 c.1919A>T.
• The reviewed variant-specific publications describe somatic cohorts and do not provide affected-family non-segregation data; consequently they cannot establish BS4.

Still missing

• An informative family with affected members is not documented.
• Genotype results for affected relatives are not available.
• Phenocopy and alternative-pathogenic-variant assessment is not available.

Sources

Reasoning

The available evidence does not document this variant in an affected germline proband with a pathogenic variant in trans in a fully penetrant dominant disorder, nor does it document a pathogenic variant in cis in any inheritance pattern. The reviewed Y640F reports concern somatic disease and provide no cis/trans germline phase data. Consequently, BP2 cannot be assessed.

Rule

Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.

Evidence considered

• PMID:22591296, PMID:22859607, and PMID:23926297 report somatic Y640F observations and do not report a second pathogenic germline allele in cis or trans.
• The ClinVar record contains germline submissions but no documented cis/trans pathogenic-variant pairing or segregation/phase information for this variant.

Still missing

• No affected germline proband observation with a pathogenic variant in trans is documented.
• No pathogenic variant in cis is documented.
• No parent, offspring, or other phasing data are available.

Sources

Reasoning

The governing rule is ACMG/AMP 2015: "Variant found in a case with an alternate molecular basis for disease." The available evidence describes somatic STAT3 Y640F observations in several disease cohorts but does not document an individual case in which a separate molecular diagnosis explains the disease instead of this variant. BP5 therefore cannot be assessed from the supplied case evidence.

Rule

Variant found in a case with an alternate molecular basis for disease.

Still missing

• A case report or clinical record showing the variant plus a separately established alternate molecular basis for the same disease is required.