NM_001127208.2:c.2814_2815del (p.Gln939AspfsTer32) is a frameshift deletion in exon 3 of TET2 predicted to introduce a premature termination codon at residue 970, triggering nonsense-mediated decay. Under the ClinGen SVI generic PVS1 framework (PMC6185798), this qualifies for PVS1 at very strong strength, as TET2 loss of function is an established germline disease mechanism for autoimmune lymphoproliferative syndrome-like phenotype with hematologic malignancy.1 This variant is absent from all queried population databases (gnomAD v2.1, v4.1, gnomAD-Canada), consistent with PM2 at supporting strength.2 The variant is absent from ClinVar and has no variant-specific functional studies, case-control data, or segregation data in the literature. Two papers (PMID:21057493, PMID:24315485) characterize TET2 catalytic function and structure but do not mention this specific variant.
TET2
Final classification
VUS
TET2 c.2814_2815del · p.Gln939AspfsTer32
TET2
NM_001127208.2:c.2814_2815del (p.Gln939AspfsTer32) is a frameshift deletion in exon 3 of TET2 predicted to introduce a premature termination codon at residue 970, triggering nonsense-mediated decay. Under the ClinGen SVI generic PVS1 framework (PMC6185798), this qualifies for PVS1 at very strong strength, as TET2 loss of function is an established germline disease mechanism for autoimmune lymphoproliferative syndrome-like phenotype with hematologic malignancy.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 supporting; combination = 1 very strong + 1 supporting, which maps to VUS.
Classification rationale
PVS1PM2
VUS
TET2 c.2814_2815del
PVS1 + PM2
→
VUS
1
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
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
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 = 0.06).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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
Triaged references · 2 PMIDs not cited in assessment