NM_001127208.2:c.5666C>T (p.Pro1889Leu) is a missense variant in exon 11 of TET2. This variant is extremely rare in population databases: absent from gnomAD v2.1 (0/155,736 alleles) and present at an allele frequency of 6.45×10⁻⁷ in gnomAD v4.1 (1/1,551,522 alleles), well below the 0.1% threshold for PM2 (supporting).1 Multiple in silico predictors suggest the variant is benign: REVEL score 0.398, BayesDel score -0.091, and SpliceAI predicts no splice impact (max delta = 0.00), meeting BP4 (supporting benign).2 The variant is absent from ClinVar and has no published functional data. No papers were identified that mention NM_001127208.2:c.5666C>T specifically.3 The variant has been observed in COSMIC (COSV54425537, n=4) as a somatic finding in cancer but lacks germline functional characterization. PVS1 is not applicable (missense variant, not a null variant). PS1, PM5, and BP7 are not applicable due to lack of same-residue comparators or variant type mismatch.4
TET2
Final classification
VUS
TET2 c.5666C>T · p.Pro1889Leu
TET2
NM_001127208.2:c.5666C>T (p.Pro1889Leu) is a missense variant in exon 11 of TET2.
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.5666C>T
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
pvs1_variant_assessmentpm5_candidates
Gene diagram
· NM_001127208.2 · variants mapped to exon structure
TET2
NM_001127208.2
Fetching transcript structure from UCSC…
Applied criteria · 2 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= 6.44528e-07; MAF= 0.00006%, 1/1551522 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.71879e-07; MAF= 0.00009%, 1/1146948 alleles, homozygotes = 0).
v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/155736 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/7876 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.4e-05%
· 1 / 1,551,522
0 hom
0 hom
European (non-Finnish) 1 / 1,146,948 |
8.7e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / 155,736
0 hom
0 hom
Not observed in any ancestry group.
+ 8 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.398. BayesDel score = -0.0914083.
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; COSV54425537, n = 4 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links