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TET2c.4466dupUncertain significance
Print report
Variant interpretation report

TET2 c.4466dup, p.(Asn1489LysfsTer2)

NM_001127208.2:c.4466dup NP_001120680.1:p.(Asn1489LysfsTer2) 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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

NM_001127208.2:c.4466dup is a frameshift duplication in exon 10 of 11, predicted to introduce a premature termination codon at p.(Asn1489LysfsTer2). NMD is expected as the PTC occurs well before the final exon (exon 11). TET2 loss of function is an established germline disease mechanism supported by literature (ALPS-like phenotype, hematologic malignancy). Under ClinGen SVI PVS1 framework (PMC6185798), frameshift variants in genes with established LOF disease mechanism are eligible for PVS1 at very strong strength.

PM2Supporting
PM2 · supporting

NM_001127208.2:c.4466dup is absent from gnomAD v2.1 and gnomAD-Canada and is present at an extremely low frequency in gnomAD v4.1 (1/1,550,974 alleles, AF = 6.45e-07). This allele frequency is well below the PM2 threshold of 0.1% for a gene where TET2 LOF variants are associated with disease.

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: PVS1 very strong, PM2 supporting; combination = 1 very strong + 1 supporting, 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.

SpliceAI score
0.140 maximum delta

Recorded SpliceAI maximum delta score: 0.140. 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
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

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: 2 met · 11 not met · 0 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_001127208.2:c.4466dup (p.Asn1489LysfsTer2) is a frameshift duplication in exon 10 of TET2 predicted to trigger nonsense-mediated decay, meeting PVS1 at very strong strength.

This variant is extremely rare in population databases, absent from gnomAD v2.1 and gnomAD-Canada, with a single heterozygous observation in gnomAD v4.1 (1/1,550,974 alleles, AF = 0.000064%), meeting PM2 at supporting level.

Met · 2

PVS1 Very strongNM_001127208.2:c.4466dup is a frameshift duplication in exon 10 of 11, predicted to introduce a premature termination codon at p.(Asn1489LysfsTer2). NMD is expected as the PTC occurs well before the final exon (exon 11). TET2 loss of function is an established germline disease mechanism supported by literature (ALPS-like phenotype, hematologic malignancy). Under ClinGen SVI PVS1 framework (PMC6185798), frameshift variants in genes with established LOF disease mechanism are eligible for PVS1 at very strong strength. Details ▾Hide ▴
Evidence considered
  • Frameshift duplication creates PTC at codon 1490 (p.Asn1489LysfsTer2)
  • PTC located in exon 10 of 11
  • NMD is expected
  • TET2 germline LOF mechanism supported by literature (PMID:36066697
  • PMID:40031954)
  • ClinGen SVI PVS1 generic framework (PMC6185798) confirms eligibility
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 SupportingNM_001127208.2:c.4466dup is absent from gnomAD v2.1 and gnomAD-Canada and is present at an extremely low frequency in gnomAD v4.1 (1/1,550,974 alleles, AF = 6.45e-07). This allele frequency is well below the PM2 threshold of 0.1% for a gene where TET2 LOF variants are associated with disease. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: 1 allele / 1
  • 550
  • 974 (AF = 0.000064%)
  • gnomAD-Canada v1.0: absent
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 11 · evaluated, threshold not reached

PS3 No variant-specific functional studies identified for NM_001127208.2:c.4466dup. Reviewed full-text of PMID:21057493 and PMID:24315485; both provide general TET2 functional characterization (5hmC catalytic activity, crystal structure) but neither mentions this specific variant. OncoKB annotations are somatic-curated and do not substitute for germline functional evidence. Details ▾Hide ▴
Evidence considered
  • Reviewed PMID:21057493 (full-text): TET2 catalytic activity characterized
  • variant not mentioned
  • Reviewed PMID:24315485 (full-text): TET2 crystal structure
  • OncoKB: Likely Oncogenic (somatic context) — does not meet germline PS3 threshold
Still missing
  • No variant-specific functional studies available
PS4 This variant is absent from ClinVar and COSMIC and has been observed only once in gnomAD v4.1 (1/1,550,974 alleles). No case reports or patient series link this variant to disease. PS4 requires statistically significant enrichment in affected individuals versus controls, which cannot be established from a single population allele. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 1 allele in 1
  • 550
  • 974 (AF = 6.45e-07)
  • Absent from ClinVar and COSMIC
Still missing
  • No case-control data available
Sources
gnomad_v4 ↗
PM1 This variant does not lie in a statistically significant mutational hotspot. While TET2 has well-characterized functional domains (Cys-rich, DSBH catalytic domain), PM1 is not applied to truncating variants that are already evaluated under PVS1, as the domain-level evidence is redundant with the LOF assessment. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: variant not in a statistically significant hotspot
  • Truncating variant: domain-level evidence is captured by PVS1
PP3 REVEL and BayesDel scores are unavailable for this duplication variant. SpliceAI predicts no significant splice impact (max delta = 0.14). No in silico prediction tools support a damaging effect at the protein level for this variant type. Details ▾Hide ▴
Evidence considered
  • REVEL: not applicable (non-SNV)
  • BayesDel: not applicable (non-SNV)
  • SpliceAI: max delta = 0.14 (no significant splice impact)
Still missing
  • In silico tools not designed for frameshift duplication variants
Sources
spliceai ↗
PP5 This variant has not been reported by any reputable germline classification source. It is absent from ClinVar. OncoKB classifies it as Likely Oncogenic in a somatic context, which does not constitute a germline pathogenicity classification under PP5. Details ▾Hide ▴
Evidence considered
  • ClinVar: variant absent
  • no germline classification available
  • OncoKB: Likely Oncogenic (somatic context only)
Still missing
  • No germline classification from any reputable source
Sources
clinvar ↗oncokb ↗
BA1 NM_001127208.2:c.4466dup has an allele frequency of 6.45e-07 in gnomAD v4.1, far below the BA1 threshold of 1% in any population. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF = 0.000064%
  • best subpopulation (NFE) AF = 0.000087%
Sources
gnomad_v4 ↗
BS1 NM_001127208.2:c.4466dup has an allele frequency of 6.45e-07 in gnomAD v4.1, far below the BS1 threshold of 0.3% for dominant disorders. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF = 0.000064%
Sources
gnomad_v4 ↗
BS2 Only one allele has been observed in gnomAD (v4.1), with no information on the clinical phenotype of that individual. This does not constitute observation in healthy adults at significant frequency. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: single heterozygous observation
  • phenotype unknown
Still missing
  • Phenotype of the single gnomAD carrier is unknown
Sources
gnomad_v4 ↗
BS3 No variant-specific functional studies are available for NM_001127208.2:c.4466dup. The two reviewed papers (PMID:21057493, PMID:24315485) characterize TET2 function generally but do not test this specific variant. OncoKB's somatic annotation does not constitute well-established functional evidence showing no damaging effect. Details ▾Hide ▴
Evidence considered
  • No variant-specific functional studies identified
  • PMID:21057493 and PMID:24315485: general TET2 characterization
  • variant not tested
Still missing
  • No variant-specific functional assays performed
BP4 REVEL and BayesDel are unavailable for this duplication variant. SpliceAI predicts no significant splice impact (max delta = 0.14). However, BP4 is intended for variants where multiple lines of computational evidence suggest no impact on gene product; the frameshift nature of this variant inherently predicts a deleterious effect on the protein. Available in silico evidence does not suggest benign impact. Details ▾Hide ▴
Evidence considered
  • REVEL: not applicable (non-SNV)
  • BayesDel: not applicable (non-SNV)
  • SpliceAI: max delta = 0.14 (no significant splice impact
  • but variant is a protein-truncating frameshift)
Sources
spliceai ↗
BP6 No reputable source has classified NM_001127208.2:c.4466dup as benign. The variant is absent from ClinVar. OncoKB classifies it as Likely Oncogenic (somatic), not benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: variant absent
  • no benign classification
  • OncoKB: Likely Oncogenic (somatic context)
Sources
clinvar ↗oncokb ↗
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to same amino acid changes as established pathogenic missense variants; this is a frameshift duplication, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

PS2 N/ANo de novo evidence available for NM_001127208.2:c.4466dup in any literature or database. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants. NM_001127208.2:c.4466dup is an out-of-frame (frameshift) duplication. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to novel missense variants at residues where different missense changes are known pathogenic. This is a frameshift duplication, not a missense variant. The PM5 candidate search confirmed not_applicable for this variant. Details ▾Hide ▴

No further detail was recorded.

PM6 N/ANo de novo observation reported for NM_001127208.2:c.4466dup in any literature or database. Details ▾Hide ▴

No further detail was recorded.

PP1 N/ANo family segregation data available for NM_001127208.2:c.4466dup. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This is a frameshift duplication, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

PP4 N/ANo patient phenotype or clinical data available for NM_001127208.2:c.4466dup. Details ▾Hide ▴

No further detail was recorded.

BS4 N/ANo family segregation data available for NM_001127208.2:c.4466dup. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_001127208.2:c.4466dup is itself a truncating (frameshift) variant. Details ▾Hide ▴

No further detail was recorded.

BP2 N/ANo data on observation in trans with a pathogenic variant for NM_001127208.2:c.4466dup. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions. NM_001127208.2:c.4466dup is an out-of-frame (frameshift) duplication. Details ▾Hide ▴

No further detail was recorded.

BP5 N/ANo data on co-occurrence with an alternate molecular basis for disease for NM_001127208.2:c.4466dup. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_001127208.2:c.4466dup is a frameshift duplication, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 applies to alternative missense or in-frame indel variants at the same amino acid position as an established pathogenic missense variant. NM_001127208.2:c.4466dup is a frameshift duplication. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
TET2
Transcript
NM_001127208.2
Coding (HGVS c.)
NM_001127208.2:c.4466dup
Protein (HGVS p.)
NP_001120680.1:p.(Asn1489LysfsTer2)
GRCh38
chr4:105272842 T>TA
GRCh37
chr4:106193999 T>TA

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 1 / 1,550,974 alleles AF 6.45e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.4e-07 · 1 / 1,550,974 alleles · 0 hom
European (non-Finnish)1 / 1,146,810 8.7e-07
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= 6.44756e-07; MAF= 0.00006%, 1/1550974 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.71984e-07; MAF= 0.00009%, 1/1146810 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +454 bp
0.000
SpliceAI acceptor gainat -278 bp
0.000
SpliceAI donor lossat +76 bp
0.020
SpliceAI donor gainat -126 bp
0.140
Pangolin splice lossmagnitude shown
-0.180
Pangolin splice gain
0.140

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 REVEL and BayesDel scores are unavailable for this duplication variant. SpliceAI predicts no significant splice impact (max delta = 0.14). No in silico prediction tools support a damaging effect at the protein level for this variant type. Details ▾Hide ▴
Evidence considered
  • REVEL: not applicable (non-SNV)
  • BayesDel: not applicable (non-SNV)
  • SpliceAI: max delta = 0.14 (no significant splice impact)
Still missing
  • In silico tools not designed for frameshift duplication variants
Sources
spliceai ↗
BP4 REVEL and BayesDel are unavailable for this duplication variant. SpliceAI predicts no significant splice impact (max delta = 0.14). However, BP4 is intended for variants where multiple lines of computational evidence suggest no impact on gene product; the frameshift nature of this variant inherently predicts a deleterious effect on the protein. Available in silico evidence does not suggest benign impact. Details ▾Hide ▴
Evidence considered
  • REVEL: not applicable (non-SNV)
  • BayesDel: not applicable (non-SNV)
  • SpliceAI: max delta = 0.14 (no significant splice impact
  • but variant is a protein-truncating frameshift)
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_001127208.2:c.4466dup is a frameshift duplication, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14).

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.
    Characterizes TET2 catalytic activity in converting 5-methylcytosine to 5-hydroxymethylcytosine using HEK293T cells expressing wild-type and mutant murine Tet2. Evaluates specific missense mutations (H1302Y, D1304A, H1802R, H1802Q, P1287S, W1211R, C1834D, R1817S/M) for effects on 5hmC production. NM_001127208.2:c.4466dup was not identified in this paper.
    Does not name this variant
    PMID 21057493 ↗
  • Crystal structure of TET2-DNA complex: insight into TET-mediated 5mC oxidation.
    Reports the crystal structure of human TET2 catalytic domain bound to methylated DNA at 2.02 Angstrom resolution. Characterizes the DSBH core, Cys-rich domain, zinc coordination, and CpG dinucleotide recognition. Evaluates specific missense mutations (R1896M, H1382Y/D1384V, R1261G, S1898F, W1291R, K1299E/S1303N, S1290A/Y1295A, R1262A, M1293A/Y1294A, N1387A, H1904R, Y1902A) for effects on catalytic activity and DNA binding. NM_001127208.2:c.4466dup was not identified in this paper.
    Does not name this variant
    PMID 24315485 ↗

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

gnomAD v4.1 1 / 1,550,974 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.140 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= 6.44756e-07; MAF= 0.00006%, 1/1550974 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.71984e-07; MAF= 0.00009%, 1/1146810 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14).

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 not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.