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
Final classification
VUS
PM2
TET2
c.5456T>G
p.Leu1819Ter
This variant
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
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 · 1 applied · 21 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 · 1
Strength
Supporting
Moderate
Strong
Very strong
PM2
moderate
review
Pathogenic
This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 2/1,551,664 alleles (AF 0.00013%; highest population AF 0.00017%; grpmax FAF 2.9e-07), which is below the 0.1% PM2 threshold.
gnomAD v2.1 absentgnomAD v4.1 ultra-rare frequency
Assessed · not applied
· 5 not met · 16 not assessed
Pathogenic
PVS1
Germline loss of function is supported as a disease mechanism for TET2, and this variant is a nonsense change.
PS1
No previously established pathogenic variant causing the same amino acid change was identified in the reviewed sources.
PS2
No de novo occurrence data with confirmed maternity and paternity were identified for this variant.
PS3
Published studies and curated oncology resources support that loss of TET2 function is biologically relevant, but no variant-specific functional assay for p.(Leu1819Ter) was identified, so PS3 cannot be applied from the current evidence.
PS4
No case-control data or clear enrichment of this exact variant in affected individuals were identified.
PM1
Available hotspot review did not identify this variant in a statistically significant hotspot or other well-established critical region without benign variation.
PM6
No assumed de novo report for this variant was identified.
PP1
No segregation data in affected relatives were identified for this variant.
PP3
Computational evidence does not independently support a damaging effect beyond the known stop-gain consequence.
PP4
No patient-specific phenotype information was provided to assess whether the clinical presentation is highly specific for a TET2-related disorder.
PP5
No pathogenic assertion from a reputable external clinical source was identified in the reviewed materials, and the variant is absent from ClinVar.
Benign
BA1
The observed population frequency does not meet the benign stand-alone threshold.
BS1
The observed population frequency does not meet the strong benign threshold.
BS2
No evidence was identified showing this variant in healthy adult individuals in a context sufficient to support BS2.
BS3
No well-established functional study demonstrating a normal or benign effect for this exact variant was identified.
BS4
No family data showing lack of segregation with disease were identified for this variant.
BP2
No cis/trans phase data with another variant were identified for this case.
BP3
No evidence was identified that this variant lies in a repetitive region without known function.
BP4
Computational evidence does not support a benign effect.
BP5
No alternate molecular explanation was identified that would account for the phenotype independently of this variant.
BP6
No reputable benign classification for the exact variant was identified, and the variant is absent from ClinVar.
N/A · 6
PM3 · PM4 · PM5 · PP2 · BP1 · BP7
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