TET2 c.1254dup, p.Pro419SerfsTer24
NM_001127208.2:c.1254dup
Pathogenic
The c.1254dupT (P419Sfs*24) variant in TET2 is a truncating frameshift absent from controls with strong functional evidence of loss of enzymatic activity. Combined PVS1 (Very Strong), PS3 (Strong), and PM2 (Moderate) classify it as Pathogenic despite a single supporting benign computational criterion.
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.1254dup
Protein Change
P419Sfs*24
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 419 in gene TET2
Variant interpretation based on transcript NM_001127208.3
Genome Browser
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HGVS InputNM_001127208:c.1254dup
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 419 in gene TET2
Functional Summary
The TET2 P419Sfs*24 variant is a truncating mutation that disrupts the C-terminal catalytic domain of the TET2 protein, a tumor suppressor and DNA demethylase. This disruption is predicted to cause gene inactivation, leading to a loss of enzymatic function necessary for generating 5-hydroxymethylcytosine (5-hmC). Functional evidence supports that this variant is likely oncogenic, contributing to hematologic malignancies by abrogating TET2's enzymatic activity.
Database Previews
OncoKB
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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 for PVS1 is: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease'. The evidence for this variant shows: NM_001127208.2:c.1254dupT is a frameshift resulting in a premature stop codon and predicted loss of function via NMD in TET2, a gene where LoF is established as pathogenic. Therefore, this criterion is applied at Very Strong strength because the variant is a null frameshift in a LoF gene.
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 is a frameshift (P419Sfs*24), not a missense change matching 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 parental testing or de novo confirmation data provided. 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 assays demonstrate disruption of the C-terminal catalytic domain of TET2, loss of 5-hydroxymethylcytosine formation, and oncogenic potential in hematologic contexts. Therefore, this criterion is applied at Strong strength because multiple well-established studies show a damaging 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 prevalence data 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'. The evidence for this variant shows: no specific hotspot or domain annotation provided beyond general catalytic domain disruption. 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)'. The evidence for this variant shows: not observed in gnomAD, ExAC, 1000 Genomes, or other population databases. Therefore, this criterion is applied at Moderate strength because the variant is absent from large control datasets.
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: no evidence of compound heterozygosity or trans-occurrence in a recessive context, and TET2 disease mechanism is haploinsufficiency. 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: frameshift rather than in-frame change; PVS1 applies instead. 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 is a frameshift, not a missense. 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 de novo or parental data provided. 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 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'. The evidence for this variant shows: it is a frameshift, not a 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: in silico tools (SpliceAI max score 0.01) do not predict deleterious splicing impact. 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'. The evidence for this variant shows: no detailed phenotype or family history 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'. The evidence for this variant shows: not reported in ClinVar or other databases. 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 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 for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: absent in controls. 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 occurrence in healthy individuals. 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 effect. 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. 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 LoF frameshift, 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 configuration 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 frameshift, 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'. The evidence for this variant shows: SpliceAI maximum score 0.01 indicating minimal splicing impact. Therefore, this criterion is applied at Supporting strength because computational analyses predict no splicing 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 alternate molecular diagnosis 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'. The evidence for this variant shows: no such reports. 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 frameshift. Therefore, this criterion is not applied.