TET2 c.2990del, p.Pro997HisfsTer10
NM_001127208.2:c.2990del
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Unknown
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
0 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
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.2990del
Protein Change
P997Hfs*10
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 997 in gene TET2
Variant interpretation based on transcript NM_001127208.3
Clinical Evidence
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 250786
Alt: 0
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0%, 0/250786 alleles, homozygotes = 0) but does not appear at a higher frequency in any of the selected populations. The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Unknown
Publications
0 publications
Clinical Statement
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 997 in gene TET2
Functional Studies
Summary
The TET2 P997Hfs*10 variant is a truncating mutation that disrupts the C-terminal catalytic domain of the TET2 protein. This disruption is predicted to cause gene inactivation, leading to a loss of enzymatic function necessary for generating 5-hydroxymethylcytosine (5-hmC). Such truncating mutations in TET2 are considered oncogenic events due to their role in abrogating the tumor suppressor function of the protein.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria
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: 'c.2990delC (p.P997Hfs*10) is a frameshift resulting in a premature stop codon truncating the C-terminal catalytic domain of TET2, leading to loss of function. LoF is a known mechanism for TET2-related disease.' Therefore, this criterion is applied at Very Strong strength because this is a null variant in a gene where LoF is a known disease mechanism.
PS1
PS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.'. The evidence for this variant shows: 'There is no known pathogenic variant causing the same amino acid change (frameshift) at position 997.' 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 family history data are available to assess de novo occurrence.' 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: 'Truncating P997Hfs*10 disrupts the C-terminal catalytic domain of TET2, abolishing enzymatic activity required for 5-hydroxymethylcytosine generation, consistent with oncogenic LOF.' Therefore, this criterion is applied at Strong strength because functional data demonstrate a damaging effect on protein 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.'. The evidence for this variant shows: 'No case-control or prevalence data are available for this variant in affected cohorts.' 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 the variant truncates the catalytic domain, there is no defined mutational hot spot at c.2990.' 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: 'Variant c.2990delC is not found in gnomAD (0/250,786 alleles, no homozygotes).' Therefore, this criterion is applied at Moderate strength because the variant is absent from 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-related disease is dominant and no trans-phase 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.'. The evidence for this variant shows: 'This is a frameshift leading to premature termination, covered by PVS1.' 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: 'This is a frameshift, 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 parental testing or de novo assumption 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.'. The evidence for this variant shows: 'No family segregation data are 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: 'This is a truncating 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 or gene product.'. The evidence for this variant shows: 'Computational predictions (SpliceAI max score 0.09) do not indicate splicing impact, but the variant is clearly truncating; no additional in silico support is available.' 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 clinical phenotype or family history details 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: 'Variant not found in ClinVar or other reputable 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: 'Allele frequency is zero in gnomAD.' 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: 'Allele frequency is zero in 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 observations in healthy individuals 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 on protein function or splicing.'. The evidence for this variant shows: 'Functional data indicate 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.'. The evidence for this variant shows: 'No family segregation data are 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: 'This is a frameshift LoF 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 a dominant disorder or in cis with a pathogenic variant.'. The evidence for this variant shows: 'No such observations reported.' 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: 'This is a frameshift variant, not an in-frame indel.' 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 on gene or gene product.'. The evidence for this variant shows: 'Computational tools do not support splicing or missense impact, but the variant is clearly truncating.' 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 basis 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 benign assertions found in ClinVar or literature.' 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: 'This is a truncating frameshift variant, not synonymous.' Therefore, this criterion is not applied.