This variant is present at extremely low frequency in population databases, with gnomAD v2.1 allele frequency of 0.006% and v4.1 allele frequency of 0.004%, both below the 0.1% threshold for PM2 at supporting strength.1 Multiple in silico predictors consistently suggest a benign impact: REVEL score 0.272 (below 0.5 threshold), BayesDel score -0.267 (benign range), and SpliceAI max delta 0.00 (no predicted splice alteration), meeting BP4 at supporting benign strength.2 No variant-specific functional studies, de novo observations, segregation data, case-control data, or pathogenic ClinVar classifications were identified. The variant is a missense change (p.Gly1519Arg) outside of any established mutational hotspot or critical functional domain.3 With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and insufficient for classification beyond Uncertain significance.
TET2
Final classification
VUS
TET2 c.4555G>A · p.Gly1519Arg
TET2
This variant is present at extremely low frequency in population databases, with gnomAD v2.1 allele frequency of 0.006% and v4.1 allele frequency of 0.004%, both below the 0.1% threshold for PM2 at supporting strength.
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 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
TET2 c.4555G>A
PM2 + BP4
→
VUS
Gene diagram
· NM_001127208.2 · variants mapped to exon structure
TET2
NM_001127208.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF 0.00623% (9/144,414 alleles), gnomAD v4.1 AF 0.00416% (64/1,537,566 alleles), both well below the 0.1% PM2 threshold. Absent from gnomAD-Canada. No homozygotes observed. Highest subpopulation AF is 0.050% (Remaining/Middle Eastern), still below the 0.1% cutoff.
gnomAD v2.1: AF=6.23e-05 (9/144414)0 homozygotes
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on gene product. REVEL score 0.272 is well below the 0.5 threshold for predicted deleteriousness. BayesDel score -0.267 falls in the benign range. SpliceAI predicts no splice alteration (max delta 0.00). Three independent in silico predictors consistently suggest a benign effect.
REVEL 0.272 (<0.5benign). BayesDel -0.267 (negativebenign range). SpliceAI max delta 0.00 (no predicted splice impact). Three concordant benign predictions.
Assessed · not applied
Pathogenic
PS1
No evidence of a different nucleotide change at amino acid position 1519 having been previously established as pathogenic.
PS2
No de novo observation data available.
PS3
No variant-specific functional studies identified.
PS4
No case-control data demonstrating enrichment in affected individuals versus controls.
PM1
No evidence that residue 1519 lies within a well-established critical functional domain or mutational hotspot.
PM6
No de novo observation data available.
PP1
No co-segregation data available.
PP2
No HCI prior gene-level constraint data available for TET2.
PP3
Multiple lines of in silico evidence do not support a deleterious effect.
PP4
No patient phenotype data available.
PP5
ClinVar classification for this variant is Uncertain significance (Variation ID 3714180) with review status 'criteria provided, single submitter' (1-star).
Benign
BA1
gnomAD maximum allele frequency is 0.050% (v2.1 Remaining individuals) or 0.051% (v4.1 Middle Eastern), far below the 1% BA1 threshold.
BS1
gnomAD maximum allele frequency is 0.050%, below the 0.3% BS1 threshold for non-VCEP adjudication.
BS2
No homozygotes observed in gnomAD (v2.1: 0 hom; v4.1: 0 hom).
BS3
No well-established functional studies demonstrate no deleterious effect for this variant.
BS4
No segregation data available.
BP1
While TET2 has a loss-of-function disease mechanism, the disease spectrum includes both truncating and missense variants.
BP2
No evidence of this variant observed in trans with a known pathogenic variant.
BP5
No alternative molecular basis for disease was identified in this case.
BP6
ClinVar classification for this variant is Uncertain significance (VUS), not benign.
N/A · 6
PVS1 · PM3 · PM4 · PM5 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.16242e-05; MAF= 0.00416%, 64/1537566 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000508475; MAF= 0.05085%, 3/5900 alleles, homozygotes = 0); grpmax FAF= 0.00013848.
v2.1
This variant is present in gnomAD v2.1 (AF= 6.23208e-05; MAF= 0.00623%, 9/144414 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000504032; MAF= 0.05040%, 2/3968 alleles, homozygotes = 0); grpmax FAF= 1.557e-05.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0042%
· 64 / 1,537,566
0 hom · FAF 0.014%
0 hom · FAF 0.014%
Middle Eastern 3 / 5,900 |
0.051% |
Ashkenazi Jewish 10 / 27,322 |
0.037% |
Admixed American 4 / 48,706 |
0.0082% |
African/African American 4 / 72,474 |
0.0055% |
Remaining individuals 3 / 59,438 |
0.005% |
European (non-Finnish) 39 / 1,141,094 |
0.0034% |
South Asian 1 / 81,612 |
0.0012% |
+ 3 not observed (European (Finnish), Amish, East Asian)
gnomAD v2.1
0.0062%
· 9 / 144,414
0 hom · FAF 0.0016%
0 hom · FAF 0.0016%
Remaining individuals 2 / 3,968 |
0.05% |
Ashkenazi Jewish 3 / 6,978 |
0.043% |
Admixed American 2 / 22,696 |
0.0088% |
South Asian 1 / 20,006 |
0.005% |
European (non-Finnish) 1 / 56,098 |
0.0018% |
+ 3 not observed (African/African American, East Asian, European (Finnish))
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant is present in ClinVar (Variation ID: 3714180); submission details unavailable.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.272. BayesDel score = -0.266636.
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; COSV113391840, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links