TET2 c.3626T>C, p.Leu1209Pro
NM_001127208.2:c.3626T>C
COSM4766118
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Uncertain Significance (VUS)
0 publications
REVEL Score
0.782
Likely Pathogenic
COSMIC Recurrence
4 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.3626T>C
Protein Change
L1209P
Location
Exon 6
(Exon 6 of 11)
5'
Exon Structure (11 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1209 in gene TET2
Alternate Identifiers
COSM4766118
Variant interpretation based on transcript NM_001127208.3
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Uncertain Significance (VUS)
Based on 1 submitter review in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
0 publications
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories).
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 1209 in gene TET2
Functional Studies
Summary
The TET2 L1209P variant has not been functionally characterized, and its biological significance remains unknown.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.782
0.782
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Benign:
CADD: 4.73
Neutral:
Show all
VCEP Guidelines
Applied ACMG/AMP Criteria
PVS1
PVS1 (Not Applied)
Strength Modified
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.3626T>C is a missense variant (p.L1209P), not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant does not result in loss of function as required by PVS1.
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: no previously established pathogenic variant results in p.L1209P. Therefore, this criterion is not applied at Not Applied strength because there is no known pathogenic variant with the same amino acid change.
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 data available. Therefore, this criterion is not applied at Not Applied strength because de novo status cannot be confirmed.
PS3
PS3 (Not Applied)
Strength Modified
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: no functional studies have been performed for p.L1209P. Therefore, this criterion is not applied at Not Applied strength because functional evidence is lacking.
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 available. Therefore, this criterion is not applied at Not Applied strength because statistical association data are missing.
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 data indicating p.L1209 lies in a known hotspot or critical domain. Therefore, this criterion is not applied at Not Applied strength because location in a hotspot or domain is not established.
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% in gnomAD and other population databases. Therefore, this criterion is applied at Moderate strength because the variant is absent from population 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 trans configuration with another pathogenic variant. Therefore, this criterion is not applied at Not Applied strength because allelic phase information is unavailable.
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: p.L1209P does not alter protein length. Therefore, this criterion is not applied at Not Applied strength because there is no change in protein length.
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: no other pathogenic missense variants reported at residue 1209. Therefore, this criterion is not applied at Not Applied strength because no known pathogenic variant exists at this residue.
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 data available. Therefore, this criterion is not applied at Not Applied strength because de novo status is unconfirmed.
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. Therefore, this criterion is not applied at Not Applied strength because segregation analysis is lacking.
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: insufficient data on missense constraint or mechanism for TET2. Therefore, this criterion is not applied at Not Applied strength because gene-specific missense tolerance is not defined.
PP3
PP3 (Supporting)
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 (e.g., conservation, splicing impact)". The evidence for this variant shows: REVEL score = 0.78 (>0.75 threshold), computational tools predict deleterious effect. Therefore, this criterion is applied at Supporting strength because in silico analyses support a damaging impact.
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 phenotype or clinical context provided. Therefore, this criterion is not applied at Not Applied strength because phenotype specificity is unavailable.
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: ClinVar reports VUS only. Therefore, this criterion is not applied at Not Applied strength because no reputable source lists this as pathogenic.
BA1
BA1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (based on population data)". The evidence for this variant shows: MAF = 0%, far below BA1 threshold. Therefore, this criterion is not applied at Not Applied strength because the allele frequency is not too high.
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: MAF = 0%, not greater than expected. Therefore, this criterion is not applied at Not Applied strength because allele frequency is not excessive.
BS2
BS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy individual with full penetrance expected at an early age". The evidence for this variant shows: no observation in healthy controls. Therefore, this criterion is not applied at Not Applied strength because no healthy individual data are available.
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: no functional studies. Therefore, this criterion is not applied at Not Applied strength because functional data are lacking.
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 analysis performed. Therefore, this criterion is not applied at Not Applied strength because segregation information is absent.
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: TET2 disease mechanism primarily involves LoF, but gene-specific data on missense intolerance are insufficient. Therefore, this criterion is not applied at Not Applied strength because gene mechanism for missense variants is not fully defined.
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 phase information with another variant. Therefore, this criterion is not applied at Not Applied strength because allelic configuration is unknown.
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: p.L1209P is a missense change, not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength because the variant is not an in-frame deletion/insertion.
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 tools predict deleterious effect (REVEL = 0.78). Therefore, this criterion is not applied at Not Applied strength because in silico evidence indicates impact, not benign.
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 such case context provided. Therefore, this criterion is not applied at Not Applied strength because alternate molecular basis information is not available.
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 lists it as benign. Therefore, this criterion is not applied at Not Applied strength because no benign assertion exists.
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: p.L1209P is a missense variant. Therefore, this criterion is not applied at Not Applied strength because the variant is not synonymous.