Variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases, meeting PM2 at supporting strength.1 TET2 loss-of-function variants are an established germline disease mechanism; this missense variant (p.His1380Pro) occurs in a gene where truncating variants are the primary known cause of disease, meeting BP1 at supporting strength.2 Multiple computational tools predict no significant impact: BayesDel score 0.120 (benign) and SpliceAI max delta 0.00 (no splicing alteration), meeting BP4 at supporting strength.3 REVEL score of 0.657 is intermediate and does not qualify for PP3; no other pathogenic criteria are met. Overall classification: Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules (PM2_supporting + BP1_supporting + BP4_supporting).4
TET2
Final classification
Likely Benign
TET2 c.4139A>C · p.His1380Pro
TET2
Variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases, meeting 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, BP1 supporting benign, BP4 supporting benign; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.
Classification rationale
PM2
BP1BP4
Likely Benign
TET2 c.4139A>C
PM2 + BP1 + BP4
→
Likely Benign
Gene diagram
· NM_001127208.2 · variants mapped to exon structure
TET2
NM_001127208.2
Fetching transcript structure from UCSC…
Applied criteria · 3 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 · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
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 / ?
0 hom
0 hom
Not observed in any ancestry group.
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 = 0.00). REVEL score = 0.657. BayesDel score = 0.120127.
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; COSV54423180, n = 4 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links