The TET2 c.5456T>G (p.Leu1819Ter) variant has not been reported in ClinVar, and curated oncology resources identify variant-specific literature context consistent with somatic relevance.1 This variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at 2/1,551,664 alleles (AF 0.00013%; highest population AF 0.00017%), which is below the 0.1% PM2 threshold and far below benign-frequency thresholds.2 Published TET2 studies support the biological importance of TET2 loss of function, but no variant-specific functional assay for p.(Leu1819Ter) was identified.3 This nonsense change occurs in the last exon, SpliceAI predicts no significant splice impact (max delta score 0.00), REVEL was unavailable, and BayesDel score 0.288612 does not independently resolve pathogenicity for this variant.4
TET2
Final classification
VUS
TET2 c.5456T>G · p.Leu1819Ter
TET2
The TET2 c.5456T>G (p.Leu1819Ter) variant has not been reported in ClinVar, and curated oncology resources identify variant-specific literature context consistent with somatic relevance.
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 moderate; combination = 1 moderate, which maps to VUS.
Classification rationale
PM2
VUS
TET2 c.5456T>G
PM2
→
VUS
4
pvs1_variant_assessmentspliceai ↗bayesdel
Gene diagram
· NM_001127208.2 · variants mapped to exon structure
TET2
NM_001127208.2
Fetching transcript structure from UCSC…
Applied criteria · 1 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
This variant is present in gnomAD v4.1 (AF= 1.28894e-06; MAF= 0.00013%, 2/1551664 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.74372e-06; MAF= 0.00017%, 2/1146972 alleles, homozygotes = 0); grpmax FAF= 2.9e-07.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00013%
· 2 / 1,551,664
0 hom · FAF 2.9e-05%
0 hom · FAF 2.9e-05%
European (non-Finnish) 2 / 1,146,972 |
0.00017% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
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). BayesDel score = 0.288612.
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; COSV54403924, n = 4 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 2 PMIDs not cited in assessment