NM_001127208.2:c.4555G>A

TET2 · NP_001120680.1:p.(Gly1519Arg) · NM_001127208.2

GRCh37: chr4:106196222 G>A · GRCh38: chr4:105275065 G>A

Gene: TET2 Transcript: NM_001127208.2

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

TET2

Transcript

NM_001127208.2

Protein

NP_001120680.1:p.(Gly1519Arg)

gnomAD AF

4.162422946397098e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

This variant is present at extremely low frequency in population databases, with gnomAD v2.1 allele frequency of 0.006% and v4.1 allele frequency of 0.004%, both below the 0.1% threshold for PM2 at supporting strength.

Multiple in silico predictors consistently suggest a benign impact: REVEL score 0.272 (below 0.5 threshold), BayesDel score -0.267 (benign range), and SpliceAI max delta 0.00 (no predicted splice alteration), meeting BP4 at supporting benign strength.

No variant-specific functional studies, de novo observations, segregation data, case-control data, or pathogenic ClinVar classifications were identified. The variant is a missense change (p.Gly1519Arg) outside of any established mutational hotspot or critical functional domain.

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and insufficient for classification beyond Uncertain significance.

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	Missense variant (p.Gly1519Arg); does not fall into null-variant buckets (nonsense, frameshift, canonical ±1,2 splice). PVS1 generic framework not applicable to missense variants.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No evidence of a different nucleotide change at amino acid position 1519 having been previously established as pathogenic. No ClinVar or literature reports of an alternate nucleotide substitution producing p.Gly1519Arg with a pathogenic classification.	clinvar pm5_candidates
PS2	Not met	No de novo observation data available. No proband narratives or family studies were provided to assess de novo occurrence with confirmed paternity and maternity.
PS3	Not met	No variant-specific functional studies identified. OncoKB reports unknown oncogenic effect with no curated functional evidence. REVEL and BayesDel are in silico predictors, not functional data. No publications were found with experimental functional characterization of NM_001127208.2:c.4555G>A.	oncokb revel bayesdel
PS4	Not met	No case-control data demonstrating enrichment in affected individuals versus controls. A single COSMIC somatic occurrence (COSV113391840, n=1) does not constitute sufficient prevalence evidence for PS4 in the germline context.
PS5	Not met	No reputable source has recently reported this variant as pathogenic with evidence unavailable for independent evaluation. ClinVar classification is Uncertain significance by a single submitter.	clinvar
PM1	Not met	No evidence that residue 1519 lies within a well-established critical functional domain or mutational hotspot. Cancerhotspots.org reports no statistically significant hotspot at this position. Gene cache returned no annotated critical domains for TET2.
PM2	Met	This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF 0.00623% (9/144,414 alleles), gnomAD v4.1 AF 0.00416% (64/1,537,566 alleles), both well below the 0.1% PM2 threshold. Absent from gnomAD-Canada. No homozygotes observed. Highest subpopulation AF is 0.050% (Remaining/Middle Eastern), still below the 0.1% cutoff.	gnomad_v2 gnomad_v4
PM5	N/A	No same-residue pathogenic comparator variants identified. PM5 candidate harvesting returned no candidates at position 1519; classic same-residue PM5 semantics cannot be confirmed.	pm5_candidates
PM6	Not met	No de novo observation data available. PM6 requires a de novo occurrence (without confirmation of paternity and maternity), and no such data were identified for this variant.
PP1	Not met	No co-segregation data available. No family studies or pedigrees were provided to assess segregation of this variant with disease.
PP2	Not met	No HCI prior gene-level constraint data available for TET2. The HCI prior lookup returned 'gene not supported'. Without established missense constraint metrics (Z-score or equivalent), PP2 cannot be applied.
PP3	Not met	Multiple lines of in silico evidence do not support a deleterious effect. REVEL score 0.272 is well below the 0.5 threshold for predicted pathogenicity. BayesDel score -0.267 falls in the benign range. SpliceAI predicts no splice impact (max delta 0.00). Computational evidence is not supportive of pathogenicity.	revel bayesdel spliceai
PP4	Not met	No patient phenotype data available. PP4 requires a phenotype or family history highly specific for the disease, and no proband clinical information was provided.
PP5	Not met	ClinVar classification for this variant is Uncertain significance (Variation ID 3714180) with review status 'criteria provided, single submitter' (1-star). PP5 requires a 3-star expert panel classification as pathogenic, which is not met.	clinvar
BA1	Not met	gnomAD maximum allele frequency is 0.050% (v2.1 Remaining individuals) or 0.051% (v4.1 Middle Eastern), far below the 1% BA1 threshold. This variant is not common enough to stand as benign.	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD maximum allele frequency is 0.050%, below the 0.3% BS1 threshold for non-VCEP adjudication. The variant is absent or too rare to meet BS1.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygotes observed in gnomAD (v2.1: 0 hom; v4.1: 0 hom). BS2 requires observation in the homozygous state in healthy controls, which is not met.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrate no deleterious effect for this variant. In silico predictions (REVEL 0.272, BayesDel -0.267) do not constitute well-established functional evidence required for BS3. No variant-specific experimental assays were identified in the literature.	revel bayesdel oncokb
BS4	Not met	No segregation data available. BS4 requires lack of segregation with disease in affected family members, and no family studies were provided.
BP1	Not met	While TET2 has a loss-of-function disease mechanism, the disease spectrum includes both truncating and missense variants. The literature describes heterozygous germline TET2 missense and LOF variants in patients with ALPS-like phenotype and hematologic malignancy (PMID: 36066697, 40031954). Insufficient evidence that only truncating variants cause disease.	pvs1_gene_context
BP2	Not met	No evidence of this variant observed in trans with a known pathogenic variant. No phase data or variant combinations were reported.
BP4	Met	Multiple lines of computational evidence suggest no impact on gene product. REVEL score 0.272 is well below the 0.5 threshold for predicted deleteriousness. BayesDel score -0.267 falls in the benign range. SpliceAI predicts no splice alteration (max delta 0.00). Three independent in silico predictors consistently suggest a benign effect.	revel bayesdel spliceai
BP5	Not met	No alternative molecular basis for disease was identified in this case. BP5 requires observation of a pathogenic variant in a different gene that explains the phenotype, and no such data were provided.
BP6	Not met	ClinVar classification for this variant is Uncertain significance (VUS), not benign. Review status is single submitter (1-star). BP6 requires a 3-star expert panel benign classification, which is not met.	clinvar
BP7	N/A	This is a missense variant (c.4555G>A, p.Gly1519Arg), not a synonymous variant. BP7 applies exclusively to synonymous (silent) variants with no predicted splice impact.
BP3	N/A	Skipped per directive — trivially not applicable.
PM3	N/A	Skipped per directive — trivially not applicable.
PM4	N/A	Skipped per directive — trivially not applicable.

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