TET2 c.3765C>G, p.Tyr1255Ter
NM_001127208.2:c.3765C>G
COSM1737964
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Unknown
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
5 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
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
| ID | Status | Details |
|---|---|---|
| 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)
5'
Exon Structure (11 total)
3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM1737964
Variant interpretation based on transcript NM_001127208.3
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is rare in the population (0.000000% MAF).
Classification
Unknown
Publications
0 publications
Clinical Statement
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
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 Evidence
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.80
VCEP Guidelines
Applied ACMG/AMP Criteria
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.