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 applied · 16 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
NM_001127208.2:c.2814_2815del is a frameshift variant predicted to result in a premature termination codon at residue 970 (p.Gln939AspfsTer32) in exon 3 of 11 exons, well upstream of the last exon-exon junction, and is predicted to trigger nonsense-mediated decay. TET2 loss of function is established as a germline disease mechanism for an autoimmune lymphoproliferative syndrome-like phenotype with hematologic malignancy. Under the ClinGen SVI PVS1 framework (PMC6185798), this frameshift variant qualifies for PVS1 at very strong strength.
Frameshift variant p.Gln939AspfsTer32 in exon 3/11 with PTC at codon 970predicted to trigger NMD per PMC6185798 criteriaTET2 germline loss-of-function established as disease mechanism for ALPS-like phenotype and hematologic malignancy (PMID:36066697
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, consistent with PM2 under generic ACMG/AMP criteria (allele frequency <0.1% in all populations).
Absent from gnomAD v2.1 (0 alleles)Absent from gnomAD v4.1 (0 alleles)Absent from gnomAD-Canada v1.0 (0 alleles)
Assessed · not applied
Pathogenic
PS2
No de novo data are available for this variant.
PS3
No variant-specific functional studies were identified.
PS4
No case-control or prevalence data are available for this variant.
PM1
This variant is located in exon 3, encoding the N-terminal region of TET2 (codon 939 of 2003), upstream of the well-characterized C-terminal catalytic domain (Cys-rich and DSBH domains, approximately residues 1129-1936).
PM6
No de novo data are available for this variant.
PP1
No segregation data are available for this variant.
PP3
SpliceAI predicts no significant splice impact (max delta score 0.06, well below the 0.2 threshold).
PP4
No patient-specific phenotype data are available for this variant.
Benign
BA1
This variant is absent from gnomAD population databases; allele frequency is 0%, far below the BA1 threshold of >5%.
BS1
This variant is absent from gnomAD; allele frequency is 0%, below the BS1 threshold of >0.3% for non-VCEP assessment.
BS2
No data are available on observation of this variant in healthy adults.
BS3
No variant-specific functional studies demonstrating no deleterious effect were identified.
BS4
No segregation data are available for this variant.
BP2
No data are available on observation of this variant in trans with a pathogenic variant.
BP4
SpliceAI predicts no splice impact (max delta 0.06), but REVEL and BayesDel scores are not available for this deletion.
BP5
No data are available on observation of this variant in a case with an alternate molecular cause.
N/A · 10
PS1 · PM3 · PM4 · PM5 · PP2 · PP5 · BP1 · BP3 · BP6 · BP7
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