NM_001127208.2:c.3796A>T (p.Asn1266Tyr) is a missense variant in exon 6 of TET2. It is absent from gnomAD population databases (0/1,551,256 alleles) and from ClinVar.1 The variant meets PM2 at supporting strength due to complete absence from large population cohorts.2 In silico predictions are conflicting: REVEL score of 0.707 is indeterminate; BayesDel score of 0.152 does not support pathogenicity; SpliceAI predicts no splicing impact (max delta=0.01). PP3 and BP4 are not met.3 No variant-specific functional studies, de novo reports, segregation data, case-control comparisons, or ClinVar classifications are available for this variant. PS3, PS2/PM6, PP1, PS4, and PP5 are all not met or not assessed.4 Under ACMG/AMP 2015 generic rules, one supporting pathogenic criterion (PM2) with no benign criteria yields a classification of Uncertain Significance.5
TET2
Final classification
VUS
TET2 c.3796A>T · p.Asn1266Tyr
TET2
NM_001127208.2:c.3796A>T (p.Asn1266Tyr) is a missense variant in exon 6 of TET2. It is absent from gnomAD population databases (0/1,551,256 alleles) and from 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 supporting; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2
VUS
TET2 c.3796A>T
PM2
→
VUS
3
revelbayesdelspliceai ↗
5
generic_acmg_combination_rules
Gene diagram
· NM_001127208.2 · variants mapped to exon structure
TET2
NM_001127208.2
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 22 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD population databases (v2.1 exomes and v4.1 genomes, combined 0/1,551,256 alleles; also absent from gnomAD-Canada v1.0), meeting the PM2 threshold of <0.1% allele frequency.
gnomAD v2.1: absentgnomAD v4.1: 0/1551
Assessed · not applied
Pathogenic
PS1
No known pathogenic variant with the same amino acid change (p.Asn1266Tyr) has been reported in ClinVar or the literature.
PS2
No de novo data with confirmed parentage are available for this variant.
PS3
No variant-specific functional studies were identified.
PS4
No case-control studies comparing variant prevalence in affected versus unaffected individuals are available.
PM1
Residue 1266 is not located within a statistically significant mutational hotspot or a well-established critical functional domain without benign variation.
PM5
No known pathogenic missense variant at amino acid residue 1266 has been identified in ClinVar.
PM6
No de novo data are available for this variant.
PP1
No co-segregation data are available for this variant.
PP2
Insufficient gene-level constraint data to determine whether TET2 has a low rate of benign missense variation.
PP3
Computational evidence is conflicting and does not meet the threshold for multiple lines of support.
PP4
No patient phenotype or clinical information is available to evaluate whether the presentation is highly specific for TET2-related germline disease.
PP5
This variant is absent from ClinVar.
Benign
BA1
Variant is absent from gnomAD population databases (AF=0% across all populations).
BS1
Variant is absent from gnomAD population databases (AF=0%).
BS2
No observations of this variant in a homozygous state or in trans with a known pathogenic TET2 variant.
BS3
No well-established functional studies demonstrating no deleterious effect are available for this variant.
BS4
No segregation data are available to evaluate lack of co-segregation with disease.
BP1
TET2 germline disease is not established to be caused exclusively by truncating variants.
BP2
No phase data are available for this variant (no observations in trans with a pathogenic variant or in cis with a pathogenic variant).
BP4
Computational evidence is conflicting and does not support a consensus benign prediction.
BP5
No data are available on an alternate molecular basis for disease in a case carrying this variant.
BP6
This variant is absent from ClinVar.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1551256 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/72994 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / 1,551,256
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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 = 0.01). REVEL score = 0.707. BayesDel score = 0.152069.
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 not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links