TET2 c.5458del, p.Ser1820ValfsTer13
NM_001127208.2:c.5458del
Pathogenic
This frameshift variant (c.5458delA; S1820Vfs*13) in TET2 is a null variant in a gene where loss of function is a known mechanism of disease (PVS1_VS), supported by functional studies demonstrating loss of catalytic activity (PS3), and absent from population databases (PM2), warranting 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.5458del
Protein Change
S1820Vfs*13
Location
Exon 11
(Exon 11 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1820 in gene TET2
Variant interpretation based on transcript NM_001127208.3
Genome Browser
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HGVS InputNM_001127208:c.5458del
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 1820 in gene TET2
Functional Summary
The TET2 S1820Vfs*13 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 to have a damaging effect, contributing to oncogenic processes in hematologic malignancies.
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 (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: NM_001127208.2:c.5458delA is a frameshift predicted to result in a premature stop codon (S1820Vfs*13) in TET2, a gene where LoF is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because the variant is a null variant 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: c.5458delA causes a frameshift leading to a premature stop, not a missense change matching a known pathogenic amino acid substitution. 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: Parental testing and family history are not available. 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 that the S1820Vfs*13 truncation disrupts the C-terminal catalytic domain of TET2, abolishing 5-hydroxymethylcytosine generation. Therefore, this criterion is applied at Strong strength because well-established functional evidence supports 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 published case-control or cohort data quantifying prevalence. 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: It is a truncating variant and PM1 is intended for missense or in-frame variants in defined hotspots. 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: c.5458delA is absent from population databases including gnomAD. Therefore, this criterion is applied at Moderate strength because it is absent from 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. The evidence for this variant shows: No data on cis/trans configuration or recessive inheritance. 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 frameshift leading to premature truncation, 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 is a frameshift variant, 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. The evidence for this variant shows: No de novo or parental data 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. The evidence for this variant shows: No familial 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 frameshift variant. 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 and SpliceAI do not predict significant impact on splicing beyond the frameshift. 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/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: It is 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: It is absent from population databases. 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 such observation 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 on protein function or splicing. The evidence for this variant shows: Functional studies demonstrate a 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 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 frameshift 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. The evidence for this variant shows: No data available on trans/cis configuration. 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. 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. The evidence for this variant shows: Computational data are inconclusive but functional data show damaging effect. 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. 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: Not reported as 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 not synonymous. Therefore, this criterion is not applied.