Starting

Initialising…

TET2

Final classification

Likely Pathogenic

TET2 c.1452T>A · p.Cys484Ter

TET2

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

Gene

TET2

Transcript

NM_001127208.2

HGVS · transcript:coding

NM_001127208.2:c.1452T>A

Consequence

N/A

GRCh38

chr4:105235394 T>A

GRCh37

chr4:106156551 T>A

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 supporting; combination = 1 very strong + 1 supporting, which maps to Likely Pathogenic. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 supporting; combination = 1 very strong + 1 supporting, which maps to Likely Pathogenic.

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

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

TET2 NM_001127208.2

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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