The TET2 c.2926C>T (p.Gln976Ter; p.Q976*) variant has been reported in curated somatic cancer resources and has not been reported in ClinVar.1 This variant is present at very low frequency in population databases, with allele frequency 7.96388e-06 in gnomAD v2.1 and 2.47815e-06 in gnomAD v4.1, both below the PM2 threshold.2 Available gene-level studies support TET2 loss-of-function biology and structural importance of the C-terminal catalytic region, but no variant-specific functional assay for p.(Gln976Ter) was identified.3 Computational review showed no significant predicted splice effect by SpliceAI, with a maximum delta score of 0.01; REVEL was unavailable, and BayesDel score 0.294732 did not provide sufficient support for PP3 or BP4 for this nonsense variant.4
Final classification
Likely Pathogenic
PVS1PM2
TET2
c.2926C>T
p.Gln976Ter
This variant
The TET2 c.2926C>T (p.Gln976Ter; p.Q976*) variant has been reported in curated somatic cancer resources and has not been reported in 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: PVS1 very strong, PM2 supporting; combination = 1 very strong + 1 supporting, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
TET2 c.2926C>T
PVS1 + PM2
→
Likely Pathogenic
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_001127208.2 · variants mapped to exon structure
TET2
NM_001127208.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 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
PVS1
very strong
Pathogenic
This variant is a nonsense change, p.(Gln976Ter), in TET2. Available gene-level evidence supports loss of function as a germline disease mechanism for TET2, and the generic PVS1 framework is eligible. The premature stop occurs well upstream of the terminal exon structure for this transcript, supporting a loss-of-function effect rather than a tolerated distal truncation.
Nonsense variant p.(Gln976Ter) / p.(Q976*)Generic PVS1 fallback was marked applicableTET2 loss of function was supported as a germline disease mechanism
PM2
supporting
Pathogenic
This variant is present at very low frequency in population databases. The gnomAD v2.1 allele frequency is 7.96388e-06 (2/251134 alleles), and the gnomAD v4.1 allele frequency is 2.47815e-06 (4/1614108 alleles), both below the 0.1% PM2 threshold.
gnomAD v2.1 AF 7.96388e-06gnomAD v4.1 AF 2.47815e-06No homozygotes observed
Assessed · not applied
· 4 not met · 15 not assessed
Pathogenic
PS1
No evidence was identified for a different nucleotide change producing the same amino acid consequence with an established pathogenic classification, so PS1 could not be assessed.
PS2
No confirmed de novo occurrence with parental confirmation was identified for this variant, so PS2 was not met.
PS3
Published TET2 studies describe gene-level functional and structural effects relevant to loss of function, but no variant-specific well-established functional assay result for p.(Gln976Ter) was identified.
PS4
This variant has not been reported in ClinVar, and no affected-case enrichment data for germline disease were identified.
PM3
No data were identified showing this variant in trans with another pathogenic variant in a recessive disease context, so PM3 could not be assessed.
PM6
No assumed de novo occurrence without full parental confirmation was identified for this variant, so PM6 was not met.
PP1
No segregation data were identified for this variant, so PP1 could not be applied.
PP3
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01.
PP4
No phenotype-specific clinical data were provided that would establish a highly specific TET2-related presentation for this individual, so PP4 could not be assessed.
PP5
This variant is absent from ClinVar, and no germline reputable-source pathogenic assertion suitable for PP5 was identified.
Benign
BA1
Population frequency does not meet BA1.
BS1
Population frequency does not meet BS1.
BS2
No evidence was identified showing this variant in healthy adult individuals at a level sufficient to apply BS2.
BS3
Available studies provide gene-level functional and structural context for TET2, but no well-established variant-specific assay showing normal function for p.(Gln976Ter) was identified.
BS4
No non-segregation data were identified for this variant, so BS4 could not be assessed.
BP2
No phase data were identified showing this variant in cis with a pathogenic variant or in trans with a pathogenic variant in a dominant condition, so BP2 could not be assessed.
BP4
Computational evidence does not support a benign interpretation.
BP5
No alternate molecular cause explaining the phenotype was identified, so BP5 could not be assessed.
BP6
This variant is absent from ClinVar, and no germline reputable-source benign assertion suitable for BP6 was identified.
N/A · 7
PM1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 2.47815e-06; MAF= 0.00025%, 4/1614108 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 1.56172e-05; MAF= 0.00156%, 1/64032 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.96388e-06; MAF= 0.00080%, 2/251134 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 4.62022e-05; MAF= 0.00462%, 1/21644 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00025%
· 4 / 1,614,108
0 hom · FAF 6.8e-05%
0 hom · FAF 6.8e-05%
European (Finnish) 1 / 64,032 |
0.0016% |
European (non-Finnish) 3 / 1,180,002 |
0.00025% |
+ 8 not observed (Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0008%
· 2 / 251,134
0 hom
0 hom
European (Finnish) 1 / 21,644 |
0.0046% |
European (non-Finnish) 1 / 113,524 |
0.00088% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, Remaining individuals, South Asian)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.294732.
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 previously been reported in somatic cancers (COSMIC; COSV105020525, n = 16 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 2 PMIDs not cited in assessment