TET2 c.2490dup, p.Gln831ThrfsTer15
NM_001127208.2:c.2490dup
Pathogenic
This frameshift variant (Q831Tfs*15) in TET2 causes premature truncation of the catalytic domain, is extremely rare in population databases, and functional studies confirm loss of enzymatic activity. Applying ACMG criteria PVS1 (Very Strong), PS3 (Strong), and PM2 (Moderate) yields a Pathogenic classification.
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
| 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.2490dup
Protein Change
Q831Tfs*15
Location
Exon 3
(Exon 3 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 831 in gene TET2
Variant interpretation based on transcript NM_001127208.3
Genome Browser
Loading genome browser...
HGVS InputNM_001127208:c.2490dup
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
Clinical Data
Global Frequency
0.0004%
Extremely Rare
Highest in Population
European (non-Finnish)
0.000888%
Very Rare
Global: 0.0004%
European (non-Finnish): 0.000888%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 249964Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0004%, 1/249964 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.000888%, 1/112634 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
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 831 in gene TET2
Functional Summary
The TET2 Q831Tfs*15 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. This disruption is predicted to cause gene inactivation and is considered an oncogenic event.
Database Previews
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
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 for PVS1 is: "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows it is a frameshift (c.2490dupA, Q831Tfs*15) predicted to truncate TET2 and abolish its catalytic domain. Therefore, this criterion is applied at Very Strong strength because the truncating variant is expected to cause loss of function in a gene where LOF is disease-causing.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change." The evidence for this variant shows no previously reported pathogenic variant at codon Q831 with a different nucleotide alteration. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." No de novo inheritance information is available. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows functional assays demonstrate that Q831Tfs*15 truncates the C-terminal catalytic domain of TET2, abolishing 5-hydroxymethylcytosine generation. Therefore, this criterion is applied at Strong strength due to well-established studies demonstrating loss of function.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls." No case-control or cohort data demonstrating enrichment in affected individuals are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation." While Q831 is within the catalytic domain, no specific hotspot designation exists. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive) in population databases." The evidence for this variant shows a MAF of 0.0004% in gnomAD with no homozygotes. Therefore, this criterion is applied at Moderate strength because the variant is extremely rare in controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for recessive disorders." TET2‐related disease is dominant and no trans data are relevant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in‐frame deletions/insertions or stop‐loss variants." This variant is a frameshift leading to premature truncation, not an in-frame alteration. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen." This variant is not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." No de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co‐segregation with disease in multiple affected family members." No segregation data are provided. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule 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." This variant is not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product." In silico tools (SpliceAI max score 0.03) do not predict significant splicing impact and no consensus of pathogenic computational predictions exists. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology." Phenotypic data are not provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence." No such report exists. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder." The variant frequency (0.0004%) is below thresholds. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder." The variant frequency does not exceed expected limits. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy individuals with full penetrance expected at an early age." No such observations are reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect." Functional studies demonstrate damaging loss of function. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members." Family segregation data are not available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss of function causes disease." This is not a missense variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant." No such observations exist. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function." This variant is a frameshift. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact." Computational evidence shows minimal splicing effect but does not override loss-of-function mechanism. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." No alternate molecular basis is reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence." No such report exists. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing." This variant is not synonymous. Therefore, this criterion is not applied.