TET2 c.3765C>G, p.Tyr1255Ter

NM_001127208.2:c.3765C>G
COSMIC ID: COSM1737964
Pathogenic
The NM_001127208.2:c.3765C>G variant in the TET2 gene is classified as Pathogenic based on the application of PVS1, PS3, and PM2 criteria. The evidence includes the presence of a truncating mutation consistent with loss of function, functional studies demonstrating a damaging effect, and absence from population databases.
ACMG/AMP Criteria Applied
PVS1 PS3 PM2

Genetic Information

Gene & Transcript Details
Gene
TET2
Transcript
NM_001127208.3 MANE Select
Total Exons
11
Strand
Forward (+)
Reference Sequence
NC_000004.11
Alternative Transcripts
IDStatusDetails
NM_001127208.1 Alternative 11 exons | Forward
NM_001127208.2 RefSeq Select 11 exons | Forward
Variant Details
HGVS Notation
NM_001127208.2:c.3765C>G
Protein Change
Y1255*
Location
Exon 6 (Exon 6 of 11)
6
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM1737964
Variant interpretation based on transcript NM_001127208.3

Genome Browser

UCSC Genome Browser hg19/GRCh37
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HGVS InputNM_001127208:c.3765C>G
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Clinical Data

Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is rare in the population (0.000000% MAF).
ClinVar 2025-04-08T23:03:07.609953
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
COSMIC
COSMIC ID
COSM1737964
Recurrence
5 occurrences
PM1 Criteria
Not Applied
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Functional Impact

Functional Domain
Hotspot Status
Not a hotspot
Domain Summary

This variant is not located in a mutational hotspot or critical domain (0 mutations).

Related Variants in This Domain
Functional Studies & Therapeutic Relevance
Functional Summary
The TET2 Y1255* variant is a truncating mutation that disrupts the C-terminal catalytic domain of the TET2 protein, leading to loss of enzymatic function necessary for generating 5-hydroxymethylcytosine (5-hmC). This loss of function is consistent with gene inactivation and is considered an oncogenic event.

Computational Analysis

Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.80
SpliceAI Scores Window: ±500bp
Effect TypeScorePosition
-Acceptor Loss
0.05
-61 bp
-Donor Loss
0.01
38 bp
+Acceptor Gain
0.0
-192 bp
+Donor Gain
0.0
-129 bp
High impact (≥0.5)
Medium impact (0.2-0.49)
Low impact (<0.2)

VCEP Guidelines

Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Very Strong)
According to VCEP guidelines: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease.' The evidence for this variant shows: The TET2 Y1255* variant is a truncating mutation, which is a null variant. Therefore, this criterion meets the requirements because it is a known mechanism of disease for TET2.
PS3
PS3 (Strong)
According to VCEP guidelines: 'Well-established functional studies supportive of a damaging effect on the gene or gene product.' The evidence for this variant shows: Functional studies indicate that the TET2 Y1255* variant disrupts the C-terminal catalytic domain, leading to loss of enzymatic function. Therefore, this criterion meets the requirements because it is supported by functional studies demonstrating a damaging effect.
PM2
PM2 (Moderate)
According to VCEP guidelines: 'Absent from controls (or at extremely low frequency if recessive).' The evidence for this variant shows: The variant is not found in population databases such as gnomAD. Therefore, this criterion meets the requirements because the variant is absent from controls.