Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_001127208.3 | MANE Select | 9589 nt | 297–6305 |
| NM_001127208.1 | Alternative | 9677 nt | 387–6395 |
| NM_001127208.2 | RefSeq Select | 9796 nt | 488–6496 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The TET2 K1877Sfs*10 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.
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -105 bp |
| Donor Loss (DL) | 0.0 | 322 bp |
| Acceptor Gain (AG) | 0.01 | 83 bp |
| Donor Gain (DG) | 0.0 | 83 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule for PVS1 is: "PVS1 – 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 or multi-exon deletion in a LoF gene)". The evidence for this variant shows a c.5630delA frameshift (K1877Sfs*10) predicted to truncate the C-terminal catalytic domain of TET2, leading to loss of enzymatic function. Therefore, this criterion is applied at Very Strong strength because this is a null variant in a gene where LoF is a known mechanism of disease.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "PS1 – Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows a frameshift rather than a known identical amino acid change with a different nucleotide alteration. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "PS2 – De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". There are no data on parentage or de novo occurrence for this case. Therefore, this criterion is not applied.
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: "PS3 – Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows that the K1877Sfs*10 truncation disrupts the TET2 catalytic domain and abolishes 5-hydroxymethylcytosine generation in functional assays, supporting a damaging effect. Therefore, this criterion is applied at Strong strength.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "PS4 – Prevalence in affected individuals significantly increased compared with controls". No case–control prevalence data are provided. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "PM1 – Located in a mutational hot spot or well-established functional domain without benign variation". While the variant truncates the catalytic domain, PVS1 already captures null effect; PM1 is not applied for truncating variants. Therefore, this criterion is not applied.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "PM2 – Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows it is not present in population databases including gnomAD (MAF = 0%). Therefore, this criterion is applied at Moderate strength.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "PM3 – Detected in trans with a pathogenic variant (for recessive disorders)". No trans-phase or recessive inheritance data are available. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "PM4 – Protein length changes due to in-frame deletions/insertions or stop-loss variants". This variant is a frameshift leading to a premature stop, covered under PVS1 rather than PM4. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "PM5 – Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". This is a frameshift, not a missense substitution. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "PM6 – Assumed de novo, but without confirmation of paternity and maternity". No de novo data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "PP1 – Co-segregation with disease in multiple affected family members". No segregation data are provided. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "PP2 – Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". This is a truncating variant, not a missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "PP3 – Multiple lines of computational evidence support a deleterious effect on the gene/gene product (e.g., conservation, splicing impact)". Computational data (SpliceAI score 0.01) do not support a significant splicing impact, and in silico predictions are not relevant for this frameshift. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "PP4 – Patient's phenotype or family history highly specific for a disease with a single genetic etiology". No phenotype or clinical context is provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "PP5 – Reputable source reports variant as pathogenic, but without accessible evidence". The variant is not reported in ClinVar or other databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "BA1 – Allele frequency is too high for the disorder (based on population data)". The variant is absent from population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "BS1 – Allele frequency is greater than expected for the disorder". The variant is not observed in controls and has MAF = 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "BS2 – Observed in healthy individuals with full penetrance expected at an early age". No such observations exist. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: "BS3 – Well-established functional studies show no damaging effect on protein function or splicing". Functional studies demonstrate loss of function, the opposite of BS3. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "BS4 – Lack of segregation in affected family members". No segregation data are presented. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "BP1 – Missense variant in a gene where only LoF causes disease". This is a loss-of-function variant, so BP1 does not apply. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "BP2 – Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". No such data are available. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "BP3 – In-frame deletions/insertions in a repetitive region without known function". This is a frameshift, not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to standard ACMG guidelines, the rule for BP4 is: "BP4 – Multiple lines of computational evidence suggest no impact". Computational evidence does not support benign effect for a truncating frameshift. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "BP5 – Variant found in a case with an alternate molecular basis for disease". No alternate molecular basis is described. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "BP6 – Reputable source reports variant as benign, but without accessible evidence". No such reports exist. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "BP7 – Synonymous variant with no predicted impact on splicing". This variant is not synonymous. Therefore, this criterion is not applied.