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LYFE SCIENCES
Project: HERA
NM_001127208.2:c.5456T>G
p.Leu1819Ter  ·  TET2
ACMG/AMP
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Initialising…
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Legacy Engine
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Classification rationale
1

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.

clinvar ↗ oncokb ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗
3

Published TET2 studies support the biological importance of TET2 loss of function, but no variant-specific functional assay for p.(Leu1819Ter) was identified.

oncokb ↗ PMID:21057493 ↗ PMID:24315485 ↗
4

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.288612.
SpliceAI ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueL1819
Hotspots ↗