The TET2 c.3784C>T (p.Arg1262Trp; p.R1262W) variant has not been reported in ClinVar.1 This variant is present at low frequency in gnomAD v2.1 and v4.1, with the highest observed frequency 0.00648% (1/15,424 alleles) in European non-Finnish individuals in gnomAD v2.1, which is below the 0.1% PM2 threshold and below the BS1 (>0.3%) and BA1 (>1%) thresholds.2 No variant-specific functional study establishing either a damaging effect or normal function was identified; the available published TET2 structural study provides protein-domain context but does not assay p.Arg1262Trp directly.3 Computational evidence is mixed overall: SpliceAI predicts no significant splice impact (max delta score 0.02), while REVEL is 0.536 and BayesDel is 0.118577, which does not provide concordant support for either PP3 or BP4.4
Final classification
VUS
PM2
TET2
c.3784C>T
p.Arg1262Trp
This variant
The TET2 c.3784C>T (p.Arg1262Trp; p.R1262W) variant has not been reported in ClinVar.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate; combination = 1 moderate, which maps to VUS.
Classification rationale
PM2
VUS
TET2 c.3784C>T
PM2
→
VUS
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_001127208.2 · variants mapped to exon structure
TET2
NM_001127208.2
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 19 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
PM2
moderate
Pathogenic
This variant is rare in population databases. In gnomAD v2.1 it was seen at 0.00319% overall (1/31,394 alleles) with a highest subpopulation frequency of 0.00648% (1/15,424 alleles), and in gnomAD v4.1 it was seen at 0.00045% overall (7/1,551,328 alleles) with a highest subpopulation frequency of 0.00244% (1/40,926 alleles); these values are below the 0.1% PM2 threshold.
gnomAD v2.1 overall AF 3.18532e-05highest subpopulation AF 6.4834e-05gnomAD v4.1 overall AF 4.51226e-06
Assessed · not applied
· 14 not met · 5 not assessed
Pathogenic
PS1
No pathogenic or likely pathogenic variant producing the same amino acid change was identified.
PS2
No confirmed de novo occurrence with established maternity and paternity was identified for this variant.
PS3
No well-established functional study showing a damaging effect of p.Arg1262Trp was identified.
PS4
No case-control enrichment data or other evidence showing this variant is significantly more common in affected individuals than in controls was identified.
PM1
Available evidence does not establish that Arg1262 lies in a mutational hotspot or a well-defined critical region without benign variation.
PM6
No presumed de novo occurrence of this variant was identified.
PP1
No segregation data were identified showing that this variant cosegregates with disease in a family.
PP2
Available evidence does not establish that TET2 is a gene in which missense variation is a common disease mechanism and benign missense variation is unusually low, so PP2 was not assessed.
PP3
Computational evidence is mixed and does not provide concordant support for a deleterious effect.
PP4
No phenotype information was provided that would allow assessment of whether the clinical presentation is highly specific for a TET2-related disorder.
Benign
BA1
Population frequency does not meet the stand-alone benign threshold.
BS1
Population frequency does not exceed the benign strong threshold.
BS2
The available population data show only rare allele observations and no homozygotes, which does not support observation in healthy adults at a level expected for BS2.
BS3
No well-established functional study showing normal or near-normal function of p.Arg1262Trp was identified.
BS4
No data were identified showing lack of segregation of this variant with disease.
BP1
Although germline loss of function is supported as a disease mechanism in TET2, the available evidence does not establish that missense variation is an uncommon pathogenic mechanism in this gene, so BP1 was not assessed.
BP2
No phase information or co-occurrence data were identified to assess BP2.
BP4
Computational evidence does not provide concordant benign support.
BP5
No phenotype data or alternate molecular diagnosis information were available to assess whether another cause fully explains the clinical presentation.
N/A · 8
PVS1 · PM3 · PM4 · PM5 · PP5 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.51226e-06; MAF= 0.00045%, 7/1551328 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.44343e-05; MAF= 0.00244%, 1/40926 alleles, homozygotes = 0); grpmax FAF= 1.28e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.18532e-05; MAF= 0.00319%, 1/31394 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.4834e-05; MAF= 0.00648%, 1/15424 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00045%
· 7 / 1,551,328
0 hom · FAF 0.00013%
0 hom · FAF 0.00013%
East Asian 1 / 40,926 |
0.0024% |
African/African American 1 / 73,004 |
0.0014% |
European (non-Finnish) 5 / 1,146,858 |
0.00044% |
+ 7 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0032%
· 1 / 31,394
0 hom
0 hom
European (non-Finnish) 1 / 15,424 |
0.0065% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.536. BayesDel score = 0.118577.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TET2, a tumor suppressor and DNA demethylase, is frequently mutated in hematologic malignancies.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54399852, n = 5 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 1 PMID not cited in assessment