Variant classification summary

NM_001127208.2:c.3765C>G

TET2 · NP_001120680.1:p.(Tyr1255Ter) · NM_001127208.2

GRCh37: chr4:106164897 C>G · GRCh38: chr4:105243740 C>G

Gene: TET2 Transcript: NM_001127208.2

Final call

Likely Pathogenic

PVS1 strong PM1 moderate PM2 supporting

Variant details

Gene

TET2

Transcript

NM_001127208.2

Protein

NP_001120680.1:p.(Tyr1255Ter)

gnomAD AF

1.2890368703216019e-06 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (strong): NM_001127208.2:c.3765C>G is a nonsense variant (p.Tyr1255Ter) in exon 6 of 11, predicted to undergo nonsense-mediated decay. TET2 loss of function is an established germline disease mechanism, with heterozygous LoF variants causing an ALPS-like phenotype with lymphoma predisposition.

2

PM1 (moderate): p.Tyr1255Ter is located within the well-characterized TET2 catalytic domain (residues 1129-1936, crystallographically resolved at 2.02 Å). Position 1255 lies in the Cys-rich domain adjacent to the critical L1 DNA-interacting loop. This truncation removes the C-terminal DSBH catalytic domain essential for 5-methylcytosine oxidation.

3

PM2 (supporting): The variant is absent from gnomAD v2.1 and present at an extremely low frequency in gnomAD v4.1 (AF=1.29e-06, 2/1,551,546 alleles, no homozygotes), well below the 0.1% threshold.

4

Overall classification: 1 strong (PVS1) + 1 moderate (PM1) + 1 supporting (PM2) meets the ACMG/AMP threshold for Likely Pathogenic.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Met	Nonsense variant NM_001127208.2:c.3765C>G (p.Tyr1255Ter) in exon 6 of 11, predicted to undergo nonsense-mediated decay, in a gene where loss of function is an established germline disease mechanism supported by multiple publications (heterozygous germline TET2 LoF variants cause an ALPS-like phenotype with lymphoma predisposition, PMID:36066697, PMID:40031954). Under ClinGen SVI PVS1 recommendations (PMC6185798), this qualifies for PVS1 at strong strength.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	Variant is a nonsense change (p.Tyr1255Ter), not a missense variant; PS1 applies only when a different nucleotide change at the same position results in the same amino acid change as a known pathogenic variant.
PS2	Not met	No de novo data for this variant is available in the case materials or literature reviewed. De novo confirmation (with maternity and paternity confirmed) is required to apply PS2.
PS3	Not met	No experimental functional data exists for the specific variant p.Tyr1255Ter or for a systematically characterized residue range that includes position 1255. The functional studies reviewed (PMID:21057493, PMID:24315485) tested selected missense residues within the TET2 catalytic domain but did not include Y1255 or any truncating variant, and the sparse testing pattern does not constitute a systematic range characterization qualifying for PS3. Domain-level knowledge supports PM1 but not variant-level PS3.	PMID:21057493 PMID:24315485
PS4	Not met	No case-control data or proband counts are available for this variant. The variant is absent from ClinVar and has no documented germline observations beyond gnomAD.
PS5	Not met	No prior classification exists for p.Tyr1255Ter or any other pathogenic variant at codon 1255. The variant is absent from ClinVar, and PM5 candidate harvest found no same-residue comparator variants.	pm5_candidates
PM1	Met	Variant p.Tyr1255Ter is located within the well-characterized TET2 catalytic domain (residues 1129-1936, structurally resolved at 2.02 Å resolution in PMID:24315485). Position 1255 lies in the Cys-rich domain immediately adjacent to the L1 DNA-interacting loop (residues 1256-1273) that is critical for DNA binding and catalytic activity. The truncation at Y1255 removes the entire C-terminal DSBH catalytic domain essential for 5-methylcytosine oxidation. The TET2 catalytic domain is a well-established functional domain whose disruption is associated with myeloid malignancies.	PMID:24315485 PMID:21057493
PM2	Met	Variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=1.29e-06, 2/1,551,546 alleles, 0 homozygotes; grpmax FAF=2.9e-07), well below the 0.1% PM2 threshold for non-VCEP generic ACMG application.	gnomad_v2 gnomad_v4
PM5	Not met	No pathogenic missense variant at codon 1255 was identified. The variant is a nonsense change (p.Tyr1255Ter) and the canonical PM5 definition applies to missense variants with a different pathogenic missense at the same codon. PM5 candidate harvest found zero same-residue candidates.	pm5_candidates
PM6	Not met	No de novo data (with confirmed maternity and paternity) is available for this variant.
PP1	Not met	No co-segregation data or pedigree information is available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This variant is a nonsense change, not a missense variant.
PP3	N/A	Nonsense variant; in silico tools (REVEL, BayesDel, SpliceAI) are calibrated for missense variants and do not meaningfully assess the impact of a premature termination codon. The deleterious effect of protein truncation is already captured by PVS1.	spliceai bayesdel
PP4	Not assessed	No patient phenotype or clinical history data were provided in the case materials. PP4 requires phenotype specificity assessment, which cannot be performed without clinical context.
PP5	Not met	Variant is absent from ClinVar. No reputable source has classified this variant as pathogenic, so PP5 cannot be applied.	clinvar
BA1	Not met	Allele frequency in gnomAD v4.1 is 1.29e-06, far below the 1% BA1 threshold. Variant is absent from gnomAD v2.1 and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Allele frequency in gnomAD v4.1 is 1.29e-06, far below the 0.3% BS1 threshold for generic ACMG application.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygotes are observed in gnomAD v4.1 (0 homozygotes out of 1,551,546 alleles). BS2 requires observation in a homozygous state in a healthy adult.	gnomad_v4
BS3	Not met	No in vitro or in vivo functional studies demonstrating no damaging effect are available for this variant.
BS4	Not met	No segregation data are available. BS4 requires lack of co-segregation with disease in affected family members.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. This variant is itself a truncating (nonsense) change, so BP1 does not apply.
BP2	Not met	No observation of this variant in trans with a known pathogenic variant for TET2-related disease.
BP3	N/A	Variant is a substitution, not an in-frame deletion or insertion. BP3 applies to in-frame indels in repetitive regions without a known function.
BP4	N/A	Nonsense variant; in silico tools (REVEL, BayesDel) are calibrated for missense variants. SpliceAI max delta is 0.05, indicating no cryptic splicing impact. The benign-read of in silico scores is irrelevant for a protein-truncating variant.	spliceai bayesdel
BP5	Not met	No evidence that this variant was observed in a case with an alternate molecular basis for disease.
BP6	Not met	Variant is absent from ClinVar. No reputable source has classified this variant as benign, so BP6 cannot be applied.	clinvar
BP7	N/A	Variant is a nonsense change (c.3765C>G, p.Tyr1255Ter), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.
PM3	N/A	PM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant. TET2-related disease is autosomal dominant/heterozygous; no recessive model is established.
PM4	N/A	Variant is a nonsense substitution, not a protein-length-altering in-frame deletion/insertion or stop-loss variant. PM4 applies to non-repeat in-frame indels and stop-loss variants.

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