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
PM2BP4
TET2
c.5666C>T
p.Pro1889Leu
This variant
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 applied · 20 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is extremely rare in population databases. It is absent from gnomAD v2.1 (0/155,736 alleles) and gnomAD-Canada (0 alleles). In gnomAD v4.1, it is observed at an allele frequency of 6.45×10⁻⁷ (1/1,551,522 alleles), well below the 0.1% PM2 threshold.
gnomAD v2.1: 0/155736 alleles (0.0%)gnomAD v4.1: 1/1
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest this variant has no significant impact on the gene product. REVEL score is 0.398 (below the pathogenic threshold), BayesDel score is -0.091 (benign-leaning), and SpliceAI predicts no splice alteration (max delta = 0.00). Three independent in silico tools converge on a neutral or benign prediction.
REVEL 0.398 (<0.5benign-leaning)BayesDel -0.091 (benign-leaning)
Assessed · not applied
· 11 not met · 9 not assessed
Pathogenic
PS1
No previously established pathogenic variant at the same amino acid position (Pro1889) has been identified in ClinVar.
PS2
No de novo data (with confirmed paternity and maternity) are available for this variant.
PS3
No well-established in vitro or in vivo functional studies have been identified for this variant.
PS4
No case-control data comparing variant prevalence in affected individuals versus controls are available.
PM1
This variant does not lie in a statistically significant mutational hotspot.
PM6
No de novo data (without paternity/maternity confirmation) are available for this variant.
PP1
No cosegregation data in affected family members are available.
PP2
TET2 is not recognized as a gene with a low rate of benign missense variation.
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
No patient phenotype or family history data are available to assess specificity for TET2-related disease.
PP5
No reputable source (ClinVar, published literature) has reported this variant as pathogenic.
Benign
BA1
This variant has an allele frequency of 6.45×10⁻⁷ (0.00006%) in gnomAD v4.1, far below the 1% BA1 threshold.
BS1
This variant has an allele frequency of 6.45×10⁻⁷ in gnomAD v4.1, far below the 0.3% BS1 threshold.
BS2
No data are available regarding observation of this variant in healthy adults at an age when fully penetrant disease would be expected.
BS3
No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing have been identified for this variant.
BS4
No segregation data in affected family members are available to assess lack of cosegregation with disease.
BP1
While TET2 germline disease is associated with loss-of-function variants, the published literature describes both truncating and missense germline variants (PMID:36066697, PMID:40031954).
BP2
No data are available regarding observation of this variant in trans with a known pathogenic variant for a fully penetrant dominant disorder.
BP5
No data are available regarding an alternate molecular basis for disease in a case carrying this variant.
BP6
No reputable source has reported this variant as benign.
N/A · 3
PVS1 · PM5 · BP7
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