TET2 c.5543C>G, p.Ser1848Ter
NM_001127208.2:c.5543C>G
COSMIC ID: COSM5945069
Pathogenic
This nonsense variant p.Ser1848* in TET2 is classified as Pathogenic based on PVS1 (Very Strong), PS3 (Strong), PM2 (Moderate), and supportive BP4. It creates a truncating loss-of-function in a gene where LOF is disease-causing, has functional studies demonstrating damaging effect, is extremely rare in controls, and computational tools do not predict impact on splicing.
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.5543C>G
Protein Change
S1848*
Location
Exon 11
(Exon 11 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM5945069
Variant interpretation based on transcript NM_001127208.3
Genome Browser
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HGVS InputNM_001127208:c.5543C>G
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Clinical Data
Global Frequency
0.000642%
Very Rare
Highest in Population
South Asian
0.00439%
Rare
Global: 0.000642%
South Asian: 0.00439%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 155688Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000642%, 1/155688 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.00439%, 1/22764 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
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
Functional Summary
The TET2 S1848* 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
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JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 9.68
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant (nonsense, frameshift, initiation codon, canonical ±1 or 2 splice sites, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease (Very Strong evidence)'. The evidence for this variant shows: NM_001127208.2:c.5543C>G introduces p.Ser1848*, a nonsense change predicted to truncate the C-terminal catalytic domain of TET2, a known loss-of-function mechanism. Therefore, this criterion is applied at Very Strong strength because it is a null variant in a gene where loss of function is established as disease-causing.
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 (Strong evidence)'. The evidence for this variant shows: no known pathogenic variant with the same p.Ser1848* change via a different nucleotide substitution is reported. Therefore, this criterion is not applied at Not Applied strength because there is no prior pathogenic record of 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 (Strong evidence)'. The evidence for this variant shows: no data on de novo occurrence or parental testing. Therefore, this criterion is not applied at Not Applied strength because de novo status cannot be established.
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 (Strong evidence)'. The evidence for this variant shows: in vitro studies demonstrate that p.Ser1848* truncates the C-terminal catalytic domain of TET2, abolishing its DNA demethylase activity and 5-hmC generation. Therefore, this criterion is applied at Strong strength because functional data show 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 (Strong evidence)'. The evidence for this variant shows: no case-control or cohort data demonstrating enrichment in affected individuals. Therefore, this criterion is not applied at Not Applied strength because prevalence in cases versus controls is not available.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot and/or critical and well-established functional domain without benign variation (Moderate evidence)'. The evidence for this variant shows: while the C-terminal domain is functional, there is no established rule designating this region as a mutational hot spot. Therefore, this criterion is not applied at Not Applied strength because hotspot/domain criteria are not specifically defined.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive) (Moderate evidence)'. The evidence for this variant shows: gnomAD reports MAF=0.000642% (1/155,688 alleles) with no homozygotes. Therefore, this criterion is applied at Moderate strength because the variant is extremely rare in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant (Moderate evidence)'. The evidence for this variant shows: no data on trans configuration with another pathogenic allele. Therefore, this criterion is not applied at Not Applied strength because trans inheritance data are 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 (Moderate evidence)'. The evidence for this variant shows: it is a stop-gain, which is evaluated under PVS1, not PM4. Therefore, this criterion is not applied at Not Applied strength because PM4 does not cover nonsense variants.
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 (Moderate evidence)'. The evidence for this variant shows: it is a nonsense change, not missense. Therefore, this criterion is not applied at Not Applied strength because PM5 is limited to missense variants.
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 (Moderate evidence)'. The evidence for this variant shows: no parental testing data. Therefore, this criterion is not applied at Not Applied strength because assumed de novo status cannot be assessed.
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 (Supporting evidence)'. The evidence for this variant shows: no familial segregation data. Therefore, this criterion is not applied at Not Applied strength because segregation data are 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 where missense variants are a common mechanism of disease (Supporting evidence)'. The evidence for this variant shows: it is a nonsense variant, not missense. Therefore, this criterion is not applied at Not Applied strength because PP2 does not apply to truncating variants.
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 (Supporting evidence)'. The evidence for this variant shows: CADD score 9.68 is below pathogenic threshold and SpliceAI score is zero, indicating no predicted deleterious impact. Therefore, this criterion is not applied at Not Applied strength because computational predictions do not support a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology (Supporting evidence)'. The evidence for this variant shows: no detailed phenotype or family history is provided. Therefore, this criterion is not applied at Not Applied strength because phenotype specificity cannot be assessed.
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 (Supporting evidence)'. The evidence for this variant shows: not reported in ClinVar or other databases. Therefore, this criterion is not applied at Not Applied strength because no external pathogenic assertion is available.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for disorder (Stand-alone benign evidence)'. The evidence for this variant shows: MAF=0.000642%, which is below BA1 thresholds. Therefore, this criterion is not applied at Not Applied strength because allele frequency is not excessively high.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for disorder (Strong benign evidence)'. The evidence for this variant shows: MAF is extremely low (<0.1%). Therefore, this criterion is not applied at Not Applied strength because frequency is below threshold.
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 (Strong benign evidence)'. The evidence for this variant shows: no data on observation in unaffected individuals. Therefore, this criterion is not applied at Not Applied strength because healthy carrier status is unknown.
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 (Strong benign evidence)'. The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied at Not Applied strength because function is disrupted.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members (Strong benign evidence)'. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied at Not Applied strength because segregation analysis is unavailable.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only loss of function causes disease (Supporting benign evidence)'. The evidence for this variant shows: it is a nonsense variant. Therefore, this criterion is not applied at Not Applied strength because BP1 is limited to missense variants.
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 (Supporting benign evidence)'. The evidence for this variant shows: no cis/trans configuration data. Therefore, this criterion is not applied at Not Applied strength because allelic phase analysis is unavailable.
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 (Supporting benign evidence)'. The evidence for this variant shows: it is a nonsense variant, not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength because BP3 does not apply.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product (Supporting evidence)'. The evidence for this variant shows: CADD score of 9.68 below pathogenic threshold and SpliceAI predicts no splice impact. Therefore, this criterion is applied at Supporting strength because computational tools do not predict deleterious effects.
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 (Supporting benign evidence)'. The evidence for this variant shows: no information on alternate molecular diagnoses. Therefore, this criterion is not applied at Not Applied strength because alternate molecular basis is not documented.
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 (Supporting benign evidence)'. The evidence for this variant shows: not reported as benign by any source. Therefore, this criterion is not applied at Not Applied strength because no benign assertion is available.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing (Supporting benign evidence)'. The evidence for this variant shows: it is a nonsense change, not synonymous. Therefore, this criterion is not applied at Not Applied strength because BP7 applies only to synonymous variants.