Variant classification summary

NM_001127208.2:c.1452T>A

TET2 · NP_001120680.1:p.(Cys484Ter) · NM_001127208.2

GRCh37: chr4:106156551 T>A · GRCh38: chr4:105235394 T>A

Gene: TET2 Transcript: NM_001127208.2

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

TET2

Transcript

NM_001127208.2

Protein

NP_001120680.1:p.(Cys484Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TET2 c.1452T>A (p.(Cys484Ter)) variant has not been reported in ClinVar.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the 0.1% rarity threshold used for non-VCEP PM2 assessment.

3

This nonsense variant introduces a premature stop codon early in the coding sequence, and available gene-level evidence supports germline TET2 loss of function as a disease mechanism, supporting PVS1 application under the generic ClinGen SVI framework.

4

SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, no REVEL score was available, and the available BayesDel score was 0.122979; these computational data were reviewed but do not outweigh the independent truncating effect of the variant.

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	This variant is a nonsense change, NM_001127208.2:c.1452T>A, predicted to cause p.(Cys484Ter) / p.(C484*) in exon 3, with truncation very early in the coding sequence (codon 484 of 2003). Available gene-level evidence supports germline TET2 loss of function as a disease mechanism, and the generic ClinGen SVI PVS1 framework indicates that this type of variant is eligible for PVS1; the early position is consistent with a null effect through truncation or nonsense-mediated decay.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified that a different nucleotide change causing the same amino acid effect has already been established as pathogenic or likely pathogenic for this gene-disease context.	clinvar
PS2	Not assessed	No confirmed de novo observation with verified maternity and paternity was identified for this variant.	clinvar
PS3	Not assessed	Published TET2 functional and structural literature was identified, but the available evidence does not show a well-established functional assay result for this exact variant that can be applied directly as strong pathogenic evidence.	oncokb PMID:21057493 PMID:24315485
PS4	Not assessed	No affected-case enrichment, case-control comparison, or established excess of this exact variant in individuals with a relevant germline phenotype was identified.	clinvar
PM1	Not met	Available evidence does not place this variant in a confirmed mutational hotspot or a narrowly defined critical region without benign variation. Cancer Hotspots did not identify a significant hotspot at this residue, and the retrieved TET2 structural literature concerns the catalytic C-terminal region rather than this early truncating position.	hotspots PMID:24315485
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the non-VCEP rarity threshold of 0.1% and supports rarity in population databases.	gnomad_v2 gnomad_v4
PM3	N/A	This criterion is intended for recessive disorders with pathogenic variants observed in trans, and that evidence context was not applicable here.
PM4	N/A	This criterion applies to protein length changes such as in-frame insertions/deletions or stop-loss variants and is not applicable to this nonsense variant already addressed under PVS1.	pvs1_variant_assessment
PM5	N/A	This criterion applies to novel missense changes at an amino acid residue where a different pathogenic missense change is established, and this variant is a nonsense change.	pvs1_variant_assessment
PM6	Not assessed	No assumed de novo observation without parental confirmation was identified for this variant.	clinvar
PP1	Not assessed	No segregation data were identified for this variant in affected family members.	clinvar
PP2	N/A	This criterion applies to missense variants in genes with low rates of benign missense variation and a disease mechanism enriched for missense change, which is not applicable to this nonsense variant.	pvs1_variant_assessment
PP3	N/A	Computational splice prediction does not indicate an added splice effect, with SpliceAI max delta score 0.00, and no REVEL score was available. A BayesDel score of 0.122979 was present, but missense-style computational prediction is not the relevant basis for pathogenic scoring in this early nonsense variant, which is already addressed by PVS1.	spliceai bayesdel pvs1_variant_assessment
PP4	Not assessed	No phenotype description specific enough to establish a highly specific TET2-related clinical presentation for this individual was available for PP4 assessment.
PP5	Not assessed	No reputable pathogenic classification source with sufficient supporting details was identified for this exact variant.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and is therefore well below the benign stand-alone threshold of 1.0%.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not exceed the benign strong threshold of 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data were identified showing this variant in well-characterized healthy adult individuals for whom the relevant phenotype would be expected to be penetrant.
BS3	Not assessed	Published TET2 functional literature was identified, but the available evidence does not show a well-established normal functional result for this exact variant that could support a benign interpretation.	oncokb PMID:21057493 PMID:24315485
BS4	Not assessed	No non-segregation data were identified for this variant in a family setting.	clinvar
BP1	N/A	This criterion applies to missense variants, whereas this variant is a nonsense change.	pvs1_variant_assessment
BP2	Not assessed	No phase information or co-occurrence data with another pathogenic variant were identified.
BP3	N/A	This criterion applies to in-frame insertions or deletions in repetitive regions without known function and is not applicable to this nonsense variant.	pvs1_variant_assessment
BP4	Not met	Available computational evidence does not support a benign interpretation. SpliceAI predicts no significant splice impact with a max delta score of 0.00, but this does not offset the independent protein-truncating effect of the nonsense variant, and the available BayesDel score of 0.122979 is not benign-supporting evidence for this context.	spliceai bayesdel
BP5	Not assessed	No alternative molecular diagnosis or other clear cause of disease was identified that would make this variant an incidental finding.
BP6	Not assessed	No reputable benign classification source was identified for this exact variant.	clinvar
BP7	N/A	This criterion applies to synonymous or certain intronic variants with no predicted splice impact and is not applicable to this nonsense variant.	pvs1_variant_assessment spliceai

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