TET2 c.877_901dupAGTGAGGCCTGTGATGCTGATGATG, p.Ala301GlufsTer2

NM_001127208.2:c.877_901dupAGTGAGGCCTGTGATGCTGATGATG
Likely Pathogenic
Final classification of NM_001127208.2:c.877_901dupAGTGAGGCCTGTGATGCTGATGATG in gene TET2 is Likely Pathogenic. This classification is supported by the application of PVS1 due to the truncating nature of the variant and PM2 due to its absence in population databases, indicating it is not a common variant.
ACMG/AMP Criteria Applied
PVS1 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.877_901dupAGTGAGGCCTGTGATGCTGATGATG
Protein Change
A301Efs*2
Location
Exon 3 (Exon 3 of 11)
3
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 301 in gene TET2
Variant interpretation based on transcript NM_001127208.3

Genome Browser

UCSC Genome Browser hg19/GRCh37
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HGVS InputNM_001127208:c.877_901dupAGTGAGGCCTGTGATGCTGATGATG
Active Tracks
ConservationRefSeqClinVargnomAD
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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 2025-04-07T09:36:57.099480
Classification
Uncertain Significance (VUS)
Submitter Breakdown
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain Significance (1 clinical laboratories).
COSMIC
COSMIC ID
Unknown
Recurrence
0 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
No evidence of other pathogenic variants at position 301 in gene TET2
Functional Studies & Therapeutic Relevance
Functional Summary
The variant TET2 A301Efs*2 has not been functionally characterized in the provided sources.

Computational Analysis

Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
SpliceAI Scores Window: ±500bp
Effect TypeScorePosition
-Acceptor Loss
0.0
-112 bp
-Donor Loss
0.05
-1 bp
+Acceptor Gain
0.02
78 bp
+Donor Gain
0.0
-424 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: 'PVS1 – Null variant in a gene where loss of function (LoF) is a known mechanism of disease.' The evidence for this variant shows: it is a truncating variant (A301Efs*2) in TET2, a gene where loss of function is associated with disease. Therefore, this criterion meets the requirements because the variant is a null variant in a gene known to be affected by loss of function.
PM2
PM2 (Moderate)
According to VCEP guidelines: 'PM2 – Absent from controls (or at extremely low frequency if recessive).' The evidence for this variant shows: it is not found in population databases such as gnomAD, indicating it is absent from controls. Therefore, this criterion meets the requirements because the variant is not present in the general population.