Classification rationale

PVS1PM2 Likely Pathogenic

TET2 c.1452T>A

The TET2 c.1452T>A (p.(Cys484Ter)) variant has not been reported in ClinVar.¹ 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.² 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.³ 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.⁴

PVS1 + PM2 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗

4 spliceai ↗bayesdel

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_001127208.2 · variants mapped to exon structure

TET2 NM_001127208.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 18 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PVS1 very strong Pathogenic

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.

Nonsense variant p.(Cys484Ter) / p.(C484*)Variant lies in exon 3Predicted stop at codon 484 of 2003

pvs1_generic_framework ↗

PM2 supporting Pathogenic

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 v2.1 absentgnomAD v4.1 absentObserved population frequency effectively 0

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 4 not met · 14 not assessed

Pathogenic

PS1 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.

PS2 No confirmed de novo observation with verified maternity and paternity was identified for this variant.

PS3 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.

PS4 No affected-case enrichment, case-control comparison, or established excess of this exact variant in individuals with a relevant germline phenotype was identified.

PM1 Available evidence does not place this variant in a confirmed mutational hotspot or a narrowly defined critical region without benign variation.

PM6 No assumed de novo observation without parental confirmation was identified for this variant.

PP1 No segregation data were identified for this variant in affected family members.

PP4 No phenotype description specific enough to establish a highly specific TET2-related clinical presentation for this individual was available for PP4 assessment.

PP5 No reputable pathogenic classification source with sufficient supporting details was identified for this exact variant.

Benign

BA1 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%.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not exceed the benign strong threshold of 0.3%.

BS2 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 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.

BS4 No non-segregation data were identified for this variant in a family setting.

BP2 No phase information or co-occurrence data with another pathogenic variant were identified.

BP4 Available computational evidence does not support a benign interpretation.

BP5 No alternative molecular diagnosis or other clear cause of disease was identified that would make this variant an incidental finding.

BP6 No reputable benign classification source was identified for this exact variant.

N/A · 8 PM3 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.122979.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54411152, n = 2 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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