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
TET2
Final classification
Likely Pathogenic
TET2 c.2926C>T · p.Gln976Ter
TET2
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
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 · 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