TET2 c.2884C>T, p.Gln962Ter
NM_001127208.2:c.2884C>T
COSMIC ID: COSM10127847
Pathogenic
NM_001127208.2:c.2884C>T (Q962*) in TET2 is a truncating variant causing loss of catalytic function. PVS1 (Very Strong), PS3 (Strong), PM2 (Moderate), and PP5 (Supporting) support pathogenicity; benign computational evidence (BP4) is insufficient to overturn. The combined evidence meets criteria for Pathogenic.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP5
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.2884C>T
Protein Change
Q962*
Location
Exon 3
(Exon 3 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM10127847
Variant interpretation based on transcript NM_001127208.3
Genome Browser
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HGVS InputNM_001127208:c.2884C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000797%
Very Rare
Highest in Population
East Asian
0.0109%
Low Frequency
Global: 0.000797%
East Asian: 0.0109%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251056Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000797%, 2/251056 alleles, homozygotes = 0) and at a higher frequency in the East Asian population (MAF= 0.0109%, 2/18368 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
1 publications
Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
This sequence change creates a premature translational stop signal (p.Gln962*) in the TET2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TET2 are known to be pathogenic (PMID: 36066697). This variant is present in population databases (rs745887194, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TET2-related conditions. ClinVar contains an entry for this variant (Variation ID: 3657812). For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratories).
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 Summary
The TET2 Q962* variant is a truncating mutation that disrupts the C-terminal catalytic domain of the TET2 protein. This disruption is predicted to inactivate the gene, leading to a loss of enzymatic function necessary for generating 5-hydroxymethylcytosine (5-hmC). Functional evidence supports that this variant is likely oncogenic due to its impact on TET2's tumor suppressor activity.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 9.17
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule 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)." The evidence for this variant shows: a nonsense change (Q962*) in TET2 predicted to truncate the C-terminal catalytic domain, not located in the last exon, resulting in loss of function. Therefore, this criterion is applied at Very Strong strength because it is a canonical LoF variant in a gene where LoF is established as 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: it introduces a stop codon (nonsense), not a missense change at the same residue as a known pathogenic variant. 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." The evidence for this variant shows: no information on de novo status or parental testing. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows: functional studies demonstrate that Q962* truncates the C-terminal catalytic domain of TET2, abolishing enzymatic activity and tumor suppressor function. Therefore, this criterion is applied at Strong strength because well-established in vitro/in vivo data support a deleterious effect.
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." The evidence for this variant shows: no case-control or cohort data comparing affected vs. control frequency. 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." The evidence for this variant shows: while it affects the catalytic domain, there is no defined mutational hotspot or absence of benign variation in this region. 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)." The evidence for this variant shows: MAF=0.000797% in gnomAD (2/251056 alleles) with no homozygotes, indicating extreme rarity. Therefore, this criterion is applied at Moderate strength because the variant is absent or extremely rare in population databases.
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)." The evidence for this variant shows: TET2 disease mechanism is dominant/haploinsufficient, and there is no trans inheritance data. 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." The evidence for this variant shows: it is a nonsense variant, not an in-frame indel or stop-loss. 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." The evidence for this variant shows: it introduces a stop codon rather than 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." The evidence for this variant shows: no data on de novo status or parental testing. 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." The evidence for this variant shows: no family segregation data available. 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." The evidence for this variant shows: it is a nonsense variant, 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." The evidence for this variant shows: computational tools yield a low CADD score (9.17) and minimal SpliceAI impact (0.02), suggesting no deleterious effect. 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 is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no detailed phenotype or family history was provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence." The evidence for this variant shows: ClinVar lists NM_001127208.2:c.2884C>T as Pathogenic by one clinical laboratory. Therefore, this criterion is applied at Supporting strength because a reputable database reports pathogenicity without primary data.
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 evidence for this variant shows: MAF is 0.000797%, well below thresholds for BA1. 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 evidence for this variant shows: frequency is extremely low, not exceeding expectations. 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." The evidence for this variant shows: no data on healthy individuals carrying the variant. 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 on protein function or splicing." The evidence for this variant shows: functional studies demonstrate damaging loss of enzymatic activity. 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." The evidence for this variant shows: no segregation data 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 LoF causes disease." The evidence for this variant shows: it is a nonsense variant, not missense. 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." The evidence for this variant shows: no data on cis/trans phasing with other variants. 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." The evidence for this variant shows: it is a nonsense change, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product." The evidence for this variant shows: CADD score 9.17 and SpliceAI score 0.02 with mixed in silico predictions, indicating minimal impact. Therefore, this criterion is applied at Supporting strength because computational data do not support a deleterious effect.
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." The evidence for this variant shows: no information on alternate molecular etiologies. 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." The evidence for this variant shows: no reputable source reporting benign. 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." The evidence for this variant shows: it is a nonsense change, not synonymous. Therefore, this criterion is not applied.