TET2c.2152delLikely pathogenic

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Variant interpretation report

TET2 c.2152del, p.(Leu718PhefsTer33)

NM_001127208.2:c.2152del NP_001120680.1:p.(Leu718PhefsTer33) View identifiers

Classification

Likely pathogenic

Variant description:

No variant summary was recorded for this case.

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

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About TET2

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 very strong (pathogenic) · 1 moderate (pathogenic)
Expert rules: Not recorded
Pipeline record: 29 Jun 2026 · version 7.0.1

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): NM_001127208.2:c.2152delC is a frameshift deletion predicted to produce premature termination at codon 751 (p.Leu718PhefsTer33). TET2 has an established loss-of-function disease mechanism for germline disease: heterozygous germline TET2 loss-of-function variants are associated with autoimmune lymphoproliferative syndrome-like phenotype and hematologic malignancy. The variant is in exon 3 of 11; the premature termination codon is >55 nucleotides upstream of the last exon-exon junction, so nonsense-mediated decay is expected. Under the ClinGen SVI PVS1 generic framework (PMC6185798), frameshift variants in genes with established LOF disease mechanism are assigned PVS1 at Very Strong strength.
PM2 (moderate): This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. Under generic ACMG/AMP standards, PM2 is met when a variant is absent from or at very low frequency (<0.1%) in population databases.

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.2152delC is a frameshift deletion predicted to produce premature termination at codon 751 (p.Leu718PhefsTer33). TET2 has an established loss-of-function disease mechanism for germline disease: heterozygous germline TET2 loss-of-function variants are associated with autoimmune lymphoproliferative syndrome-like phenotype and hematologic malignancy. The variant is in exon 3 of 11; the premature termination codon is >55 nucleotides upstream of the last exon-exon junction, so nonsense-mediated decay is expected. Under the ClinGen SVI PVS1 generic framework (PMC6185798), frameshift variants in genes with established LOF disease mechanism are assigned PVS1 at Very Strong strength.

PM2Moderate

PM2 · moderate

This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. Under generic ACMG/AMP standards, PM2 is met when a variant is absent from or at very low frequency (<0.1%) in population databases.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

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 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.

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

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.040 maximum delta

Recorded SpliceAI maximum delta score: 0.040. 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 · 17 not met · 1 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_001127208.2:c.2152delC is a frameshift deletion predicted to result in premature termination at codon 751 (p.Leu718PhefsTer33) in TET2, a gene for which heterozygous germline loss-of-function variants are an established cause of an autoimmune lymphoproliferative syndrome-like phenotype and hematologic malignancy.

This variant is absent from gnomAD population databases (v2.1 exomes, v4.1 exomes/genomes, and gnomAD-Canada v1.0), indicating it is not a common benign polymorphism and supporting evidence for rarity in the general population.

Under the generic ACMG/AMP 2015 classification framework, application of PVS1 (Very Strong) for a null variant in a gene where loss of function is a known disease mechanism, together with PM2 (Moderate) for absence from population databases, yields a Likely Pathogenic classification (1 Very Strong + 1 Moderate).

Met · 2

PVS1 Very strongNM_001127208.2:c.2152delC is a frameshift deletion predicted to produce premature termination at codon 751 (p.Leu718PhefsTer33). TET2 has an established loss-of-function disease mechanism for germline disease: heterozygous germline TET2 loss-of-function variants are associated with autoimmune lymphoproliferative syndrome-like phenotype and hematologic malignancy. The variant is in exon 3 of 11; the premature termination codon is >55 nucleotides upstream of the last exon-exon junction, so nonsense-mediated decay is expected. Under the ClinGen SVI PVS1 generic framework (PMC6185798), frameshift variants in genes with established LOF disease mechanism are assigned PVS1 at Very Strong strength. Details ▾Hide ▴

Evidence considered

Frameshift null variant (c.2152del
p.Leu718PhefsTer33) predicted to trigger NMD
TET2 germline loss-of-function established as disease mechanism (PMIDs: 36066697
40031954)
Variant in exon 3
not in last exon or biologically irrelevant region

Sources

pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment

PM2 ModerateThis variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. Under generic ACMG/AMP standards, PM2 is met when a variant is absent from or at very low frequency (<0.1%) in population databases. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1
Absent from gnomAD v4.1
Absent from gnomAD-Canada v1.0

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 17 · evaluated, threshold not reached

PS2 No de novo occurrence of NM_001127208.2:c.2152delC has been reported, and maternity/paternity confirmation data are absent from all reviewed sources. Details ▾Hide ▴

Still missing

No de novo data available for this variant

PS3 No well-established functional studies of NM_001127208.2:c.2152delC were identified. The two publications reviewed (PMID:21057493, PMID:24315485) describe general TET2 biochemical function and crystal structure but do not study this specific variant. OncoKB 'Likely Oncogenic' annotation is a somatic cancer database curation and does not constitute germline functional evidence. Details ▾Hide ▴

Evidence considered

OncoKB classifies as Likely Oncogenic in somatic context — not germline functional evidence

Still missing

No variant-specific functional studies available

Sources

oncokb ↗

PS4 This variant is absent from gnomAD and ClinVar and has not been observed in affected individuals in any reviewed publication. Details ▾Hide ▴

Still missing

No affected individuals reported

PM1 The variant at codon 718 lies N-terminal to the TET2 catalytic domain (residues 1129-1936) and is not located in a mutational hotspot or well-characterized critical functional domain free of benign variation. Hotspot analysis confirms this residue is not in a statistically significant hotspot. Details ▾Hide ▴

Evidence considered

Residue 718 is outside the catalytic domain (residues 1129-1936)
Not in a statistically significant mutational hotspot

Sources

pvs1_variant_assessment

PP1 No cosegregation data are available for this variant. No family studies were identified in the reviewed literature. Details ▾Hide ▴

Still missing

No family studies or cosegregation data available

PP3 REVEL and BayesDel scores are not available for this deletion variant (not an SNV). SpliceAI predicts no significant splice impact (max delta score 0.04). No computational evidence supports a deleterious effect through in silico algorithms. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score: 0.04 (no significant splice impact)
REVEL not available for deletion variants
BayesDel not available for deletion variants

Still missing

In silico missense predictors not applicable to deletion variants

Sources

spliceai ↗

PP4 No patient phenotype or clinical presentation data are available for review. This variant has not been reported in any individual in the reviewed literature. Details ▾Hide ▴

Still missing

No clinical phenotype data available

PP5 No reputable clinical diagnostic laboratory has reported this variant as pathogenic. OncoKB 'Likely Oncogenic' is a somatic cancer database annotation and does not constitute a germline diagnostic classification from a reputable source. Details ▾Hide ▴

Evidence considered

OncoKB: Likely Oncogenic (somatic context — not a germline diagnostic classification)

Still missing

No germline clinical classification from a diagnostic laboratory

Sources

oncokb ↗

BA1 The variant is absent from gnomAD (allele frequency 0), which is far below the BA1 threshold of >1% population frequency. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: absent
gnomAD v4.1: absent
gnomAD-Canada: absent

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS1 The variant is absent from gnomAD (allele frequency 0), which does not meet the BS1 threshold of >0.3% population frequency. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: absent
gnomAD v4.1: absent
gnomAD-Canada: absent

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS2 BS2 is met when a variant is observed in a healthy adult individual for a disorder with full penetrance expected at an early age. The variant is absent from gnomAD (which includes largely healthy individuals), but absence alone does not satisfy BS2; BS2 requires observation in confirmed healthy individuals. Details ▾Hide ▴

Still missing

No observation in confirmed healthy adults

BS3 No well-established functional studies of NM_001127208.2:c.2152delC showing no damaging effect on protein function or splicing were identified in the reviewed literature. Details ▾Hide ▴

Still missing

No variant-specific functional studies available

BS4 No cosegregation data are available to demonstrate lack of segregation with disease in affected families. Details ▾Hide ▴

Still missing

No family cosegregation data available

BP2 No evidence of this variant observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern. Details ▾Hide ▴

Still missing

No co-occurrence data available

BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL and BayesDel are not available for this deletion variant. SpliceAI shows no splice impact (max delta 0.04), but a single line of computational evidence targeting splicing alone is insufficient for BP4 when the variant's primary effect is protein truncation. Details ▾Hide ▴

Evidence considered

SpliceAI max delta 0.04: no splice impact
REVEL/BayesDel not applicable to deletions

Still missing

In silico missense predictors not applicable to deletion variants

Sources

spliceai ↗

BP5 No observation of this variant in a case with an alternate molecular basis for disease has been reported. Details ▾Hide ▴

Still missing

No alternate-molecular-basis data available

BP6 No reputable source has reported this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴

Evidence considered

Absent from ClinVar — no benign classification exists

Sources

clinvar ↗

Not assessed · 1 · no assessment recorded

PM6 No de novo observation of NM_001127208.2:c.2152delC has been reported with confirmed maternity and paternity in any reviewed publication or database. Details ▾Hide ▴

Still missing

No de novo data available for this variant

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 requires the same amino acid change as a previously established pathogenic variant. This is a frameshift deletion, not a single amino acid substitution at a specific residue. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 is for protein length changes due to in-frame deletions/insertions in non-repeat regions or stop-loss variants. This variant is an out-of-frame (frameshift) deletion resulting in premature termination, which is assessed under PVS1 rather than PM4. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 requires a novel missense change at a residue where a different pathogenic missense change has been previously reported. This variant is a frameshift deletion, not a missense, and same-residue comparator semantics cannot be established from the normalized protein consequence. Details ▾Hide ▴

Sources

pm5_candidates

PP2 N/APP2 applies to missense variants in a gene with a low rate of benign missense variation and where missense variants are a common disease mechanism. This variant is a frameshift deletion, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes for which primarily truncating variants are known to cause disease. This variant is a truncating frameshift variant, not a missense, and truncating variants are the established disease mechanism in TET2. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is an out-of-frame (frameshift) deletion, not an in-frame change in a repetitive region. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is for variants observed in trans with a pathogenic variant in recessive disorders. TET2 germline disease follows an autosomal dominant inheritance pattern (heterozygous LOF variants sufficient per PMID:40031954); no recessive disease model is established for TET2. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: TET2
Transcript: NM_001127208.2
Coding (HGVS c.): NM_001127208.2:c.2152del
Protein (HGVS p.): NP_001120680.1:p.(Leu718PhefsTer33)
GRCh38: chr4:105236092 AC>A
GRCh37: chr4:106157249 AC>A

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…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in TET2 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +493 bp

0.040

SpliceAI acceptor gainat +417 bp

0.000

SpliceAI donor lossat -409 bp

0.000

SpliceAI donor gainat -217 bp

0.000

Pangolin splice lossmagnitude shown

-0.050

Pangolin splice gain

0.010

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta score: 0.04 (no significant splice impact)
REVEL not available for deletion variants
BayesDel not available for deletion variants

Still missing

In silico missense predictors not applicable to deletion variants

Sources

spliceai ↗

Evidence considered

SpliceAI max delta 0.04: no splice impact
REVEL/BayesDel not applicable to deletions

Still missing

In silico missense predictors not applicable to deletion variants

Sources

spliceai ↗

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a frameshift deletion, 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 = 0.04).

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.

Demonstrates that TET2 converts 5-methylcytosine to 5-hydroxymethylcytosine in DNA and that somatic TET2 mutations impair this catalytic activity in myeloid cancers. NM_001127208.2:c.2152delC 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.

Presents the crystal structure of the human TET2 catalytic domain bound to methylated DNA at 2.02 A resolution, revealing the structural basis for 5mC recognition and oxidation. NM_001127208.2:c.2152delC 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 Captured gnomAD v4.1 source record Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.040 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

Absent from gnomAD v4.1.

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 = 0.04).

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.