TET2 c.3777del, p.Asn1260IlefsTer6
NM_001127208.2:c.3777del
Pathogenic
The c.3777del (p.N1260Ifs*6) variant in TET2 is a frameshift leading to a premature stop in a gene known to cause disease via loss of function. It is absent from controls (PM2), functional studies demonstrate loss of enzymatic activity (PS3), and it is a predicted null variant (PVS1). Computational evidence does not support splicing impact (BP4). These findings fulfill PVS1, PS3, and PM2, meeting criteria for a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
BP4
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.3777del
Protein Change
N1260Ifs*6
Location
Exon 6
(Exon 6 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1260 in gene TET2
Variant interpretation based on transcript NM_001127208.3
Genome Browser
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HGVS InputNM_001127208:c.3777del
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 not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
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 1260 in gene TET2
Functional Summary
The TET2 N1260Ifs*6 variant is a truncating mutation that disrupts the C-terminal catalytic domain of the TET2 protein, a tumor suppressor and DNA demethylase. Functional evidence indicates that this truncation leads to the inactivation of TET2's enzymatic function, specifically impairing its ability to generate 5-hydroxymethylcytosine. This loss of function is considered an oncogenic event, contributing to the pathogenesis of hematologic malignancies.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule/finding for PVS1 is: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)'. The evidence for this variant shows: c.3777del causes a frameshift resulting in a premature stop (p.N1260Ifs*6) in TET2, a gene known to be disease‐causing via LoF. Therefore, this criterion is applied at Very Strong strength because the variant is a predicted null variant in a gene where LoF is a known mechanism of disease.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence for this variant shows: c.3777del leads to a frameshift and not the same amino acid change as any known pathogenic variant. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence for this variant shows: no data on de novo status or parental confirmation. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule/finding for PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows: in vitro functional studies demonstrate that the truncation disrupts the C-terminal catalytic domain of TET2 and abolishes its enzymatic activity. Therefore, this criterion is applied at Strong strength because well-established functional studies show a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: no statistical case-control data or prevalence information. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant shows: no specific evidence that the c.3777 region is a defined mutational hotspot separate from general loss‐of‐function. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule/finding for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: c.3777del is not observed in gnomAD or other population databases (MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM3 is: 'Detected in trans with a pathogenic variant for recessive disorders'. The evidence for this variant shows: no data on trans configuration and TET2 disease is not recessive. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows: a frameshift leading to premature stop, not an in-frame change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence for this variant shows: frameshift variant, not a missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: no data on de novo status without parental confirmation. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP1 is: 'Co-segregation with disease in multiple affected family members'. The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence for this variant shows: frameshift variant, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene/gene product'. The evidence for this variant shows: SpliceAI score of 0.03 indicating minimal splicing impact and no other in silico predictions supportive of deleterious effect. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP4 is: 'Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no detailed phenotypic information provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence for this variant shows: no entries in ClinVar or other expert repositories. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BA1 is: 'Allele frequency is too high for the disorder'. The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. The evidence for this variant shows: no observations in healthy individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing'. The evidence for this variant shows: functional studies indicate damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS4 is: 'Lack of segregation in affected family members'. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP1 is: 'Missense variant in a gene where only LoF causes disease'. The evidence for this variant shows: a frameshift variant, not missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. The evidence for this variant shows: no data on phasing with other variants. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function'. The evidence for this variant shows: frameshift variant, not in‐frame in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule/finding for BP4 is: 'Multiple lines of computational evidence suggest no impact'. The evidence for this variant shows: SpliceAI score of 0.03 indicating minimal impact on splicing and no other in silico support for deleterious effect. Therefore, this criterion is applied at Supporting strength because computational evidence does not support a functional impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: no reports of an alternate molecular basis. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. The evidence for this variant shows: no reputable benign reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP7 is: 'Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows: it is a frameshift variant, not synonymous. Therefore, this criterion is not applied.