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
TET2
Final classification
VUS
TET2 c.3784C>T · p.Arg1262Trp
TET2
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
Gene diagram
· NM_001127208.2 · variants mapped to exon structure
TET2
NM_001127208.2
Fetching transcript structure from UCSC…
Applied criteria · 1 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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