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TET2c.5456T>GUncertain significance
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Variant interpretation report

TET2 c.5456T>G, p.(Leu1819Ter)

NM_001127208.2:c.5456T>G NP_001120680.1:p.(Leu1819Ter) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About TET2

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
2 / 1,551,664 alleles

gnomAD v4.1: 2 / 1,551,664 alleles. Recorded AF 1.28894e-06. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
4 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV54403924, n = 4 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 5 not met · 16 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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.

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

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.

Met · 1

PM2 ModerateThis 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 absent
  • gnomAD v4.1 ultra-rare frequency
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 5 · evaluated, threshold not reached

PM1 Available hotspot review did not identify this variant in a statistically significant hotspot or other well-established critical region without benign variation. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots review
Still missing
  • Hotspot review was flagged for human review
  • but no hotspot evidence supporting PM1 was identified.
Sources
hotspots ↗PMID:24315485 ↗
PP3 Computational evidence does not independently support a damaging effect beyond the known stop-gain consequence. SpliceAI predicts no significant splice impact (max delta score 0.00), REVEL was unavailable, and BayesDel score 0.288612 alone is not sufficient to apply PP3 for this nonsense variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI no splice effect
  • BayesDel score 0.288612
  • REVEL unavailable
Still missing
  • No additional calibrated missense-style predictor evidence was available for this variant.
Sources
spliceai ↗bayesdel
BA1 The observed population frequency does not meet the benign stand-alone threshold. In gnomAD v4.1 the total AF is 0.00013%, which is well below the 1.0% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 allele frequency
Sources
gnomad_v4 ↗
BS1 The observed population frequency does not meet the strong benign threshold. In gnomAD v4.1 the total AF is 0.00013%, which is well below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 allele frequency
Sources
gnomad_v4 ↗
BP4 Computational evidence does not support a benign effect. SpliceAI predicts no significant splice impact (max delta score 0.00), but REVEL was unavailable and BayesDel score 0.288612 does not provide benign support for this stop-gain variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI no splice effect
  • BayesDel score 0.288612
  • REVEL unavailable
Still missing
  • No calibrated benign computational evidence for the exact variant was identified.
Sources
spliceai ↗bayesdel

Not assessed · 16 · no assessment recorded

PVS1 Germline loss of function is supported as a disease mechanism for TET2, and this variant is a nonsense change. However, c.5456T>G (p.Leu1819Ter) lies in the last exon and is predicted to truncate the final 184 of 2003 amino acids (about 9.2%), so additional review is needed to determine whether loss of this distal C-terminal region is sufficient for a generic PVS1 strength assignment. Details ▾Hide ▴
Evidence considered
  • Generic ACMG fallback framework
  • TET2 germline loss-of-function mechanism supported
  • Nonsense variant in last exon
Still missing
  • Confirm whether the last-exon truncation removes a region that is critical to TET2 function under the generic PVS1 framework.
  • Confirm whether full-strength or downgraded PVS1 is appropriate for this distal truncation.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗PMID:36066697 ↗PMID:40031954 ↗
PS1 No previously established pathogenic variant causing the same amino acid change was identified in the reviewed sources. Details ▾Hide ▴
Evidence considered
  • ClinVar query for exact variant
Still missing
  • A same-amino-acid established pathogenic comparator was not identified.
Sources
clinvar ↗
PS2 No de novo occurrence data with confirmed maternity and paternity were identified for this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar exact-variant review
Still missing
  • No parental testing or confirmed de novo report was identified.
Sources
clinvar ↗
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. Details ▾Hide ▴
Evidence considered
  • Variant-specific curated oncology literature context
  • General TET2 functional studies
Still missing
  • No direct functional assay for this exact variant was identified.
Sources
oncokb ↗PMID:21057493 ↗PMID:24315485 ↗
PS4 No case-control data or clear enrichment of this exact variant in affected individuals were identified. Details ▾Hide ▴
Evidence considered
  • ClinVar review
  • Population comparison context
Still missing
  • No affected-case series or case-control evidence for the exact variant was identified.
Sources
clinvar ↗gnomad_v4 ↗
PM6 No assumed de novo report for this variant was identified. Details ▾Hide ▴
Evidence considered
  • ClinVar exact-variant review
Still missing
  • No proband-level report suggesting de novo occurrence was identified.
Sources
clinvar ↗
PP1 No segregation data in affected relatives were identified for this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar exact-variant review
Still missing
  • No informative family segregation data were identified.
Sources
clinvar ↗
PP4 No patient-specific phenotype information was provided to assess whether the clinical presentation is highly specific for a TET2-related disorder. Details ▾Hide ▴
Still missing
  • Phenotype details and differential-diagnosis context were not available.
PP5 No pathogenic assertion from a reputable external clinical source was identified in the reviewed materials, and the variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • ClinVar review
Still missing
  • No reputable external pathogenic classification for the exact variant was identified.
Sources
clinvar ↗
BS2 No evidence was identified showing this variant in healthy adult individuals in a context sufficient to support BS2. Details ▾Hide ▴
Evidence considered
  • gnomAD population presence without phenotype data
Still missing
  • No healthy-carrier evidence was identified.
Sources
gnomad_v4 ↗
BS3 No well-established functional study demonstrating a normal or benign effect for this exact variant was identified. Details ▾Hide ▴
Evidence considered
  • General TET2 functional literature context
Still missing
  • No benign functional assay for p.(Leu1819Ter) was identified.
Sources
oncokb ↗PMID:21057493 ↗PMID:24315485 ↗
BS4 No family data showing lack of segregation with disease were identified for this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar exact-variant review
Still missing
  • No non-segregation data were identified.
Sources
clinvar ↗
BP2 No cis/trans phase data with another variant were identified for this case. Details ▾Hide ▴
Still missing
  • No phase information was available.
BP3 No evidence was identified that this variant lies in a repetitive region without known function. Details ▾Hide ▴
Still missing
  • Repeat-region context was not established.
BP5 No alternate molecular explanation was identified that would account for the phenotype independently of this variant. Details ▾Hide ▴
Still missing
  • Case-level alternate-cause analysis was not available.
BP6 No reputable benign classification for the exact variant was identified, and the variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • ClinVar review
Still missing
  • No reputable external benign classification for the exact variant was identified.
Sources
clinvar ↗
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/ANo recessive inheritance context or trans observations relevant to PM3 were identified for this variant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AThis is a nonsense variant rather than an in-frame length change, so PM4 is not the appropriate criterion. Details ▾Hide ▴
Evidence considered
  • Variant consequence review
Sources
pvs1_variant_assessment
PM5 N/AClassic same-residue PM5 logic could not be confirmed safely for this case, and no validated comparator variants were identified for application of PM5. Details ▾Hide ▴
Evidence considered
  • PM5 candidate review
Sources
pm5_candidates
PP2 N/AThis criterion is intended for missense variation in genes with a low rate of benign missense variation and a common pathogenic missense mechanism. This variant is a nonsense change. Details ▾Hide ▴

No further detail was recorded.

BP1 N/AThis criterion applies to missense variants in genes where truncating variants are the predominant pathogenic mechanism. This variant is a nonsense change. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous or certain intronic variants with no predicted splice impact. This variant is a nonsense change. Details ▾Hide ▴
Evidence considered
  • Variant consequence review
  • SpliceAI review
Sources
spliceai ↗

Identifiers

Gene
TET2
Transcript
NM_001127208.2
Coding (HGVS c.)
NM_001127208.2:c.5456T>G
Protein (HGVS p.)
NP_001120680.1:p.(Leu1819Ter)
GRCh38
chr4:105275966 T>G
GRCh37
chr4:106197123 T>G
COSMIC
COSV54403924

Gene diagram

Every interpreted variant in TET2, mapped onto the exon structure of NM_001127208.2. Select a row to find it on the plot.

TET2NM_001127208.2
Fetching transcript structure from UCSC…
gnomAD v4.1 2 / 1,551,664 alleles AF 1.29e-06 · 0 homozygotes · FAF 2.9e-07
gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.3e-06 · 2 / 1,551,664 alleles · 0 hom · FAF 2.9e-07
European (non-Finnish)2 / 1,146,972 1.7e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD 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.

gnomAD v2.1

Absent from gnomAD v2.1.

SpliceAI and Pangolin

SpliceAI acceptor lossat +254 bp
0.000
SpliceAI acceptor gainat -15 bp
0.000
SpliceAI donor lossat -477 bp
0.000
SpliceAI donor gainat +14 bp
0.000
Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.020

Other predictors

REVEL
Not available
BayesDel
0.289

How the predictions were used

PP3 Computational evidence does not independently support a damaging effect beyond the known stop-gain consequence. SpliceAI predicts no significant splice impact (max delta score 0.00), REVEL was unavailable, and BayesDel score 0.288612 alone is not sufficient to apply PP3 for this nonsense variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI no splice effect
  • BayesDel score 0.288612
  • REVEL unavailable
Still missing
  • No additional calibrated missense-style predictor evidence was available for this variant.
Sources
spliceai ↗bayesdel
BP4 Computational evidence does not support a benign effect. SpliceAI predicts no significant splice impact (max delta score 0.00), but REVEL was unavailable and BayesDel score 0.288612 does not provide benign support for this stop-gain variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI no splice effect
  • BayesDel score 0.288612
  • REVEL unavailable
Still missing
  • No calibrated benign computational evidence for the exact variant was identified.
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous or certain intronic variants with no predicted splice impact. This variant is a nonsense change. Details ▾Hide ▴
Evidence considered
  • Variant consequence review
  • SpliceAI review
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.288612.

2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2.
    No paper-specific finding is recorded.
    PMID 21057493 ↗
  • Crystal structure of TET2-DNA complex: insight into TET-mediated 5mC oxidation.
    No paper-specific finding is recorded.
    PMID 24315485 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 2 / 1,551,664 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.288612.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54403924, n = 4 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.