TET2c.2926C>TLikely pathogenic

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Variant interpretation report

TET2 c.2926C>T, p.(Gln976Ter)

NM_001127208.2:c.2926C>T NP_001120680.1:p.(Gln976Ter) 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 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 13 May 2026

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): This variant is a nonsense change, p.(Gln976Ter), in TET2. Available gene-level evidence supports loss of function as a germline disease mechanism for TET2, and the generic PVS1 framework is eligible. The premature stop occurs well upstream of the terminal exon structure for this transcript, supporting a loss-of-function effect rather than a tolerated distal truncation.
PM2 (supporting): This variant is present at very low frequency in population databases. The gnomAD v2.1 allele frequency is 7.96388e-06 (2/251134 alleles), and the gnomAD v4.1 allele frequency is 2.47815e-06 (4/1614108 alleles), both below the 0.1% PM2 threshold.

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

This variant is a nonsense change, p.(Gln976Ter), in TET2. Available gene-level evidence supports loss of function as a germline disease mechanism for TET2, and the generic PVS1 framework is eligible. The premature stop occurs well upstream of the terminal exon structure for this transcript, supporting a loss-of-function effect rather than a tolerated distal truncation.

PM2Supporting

PM2 · supporting

This variant is present at very low frequency in population databases. The gnomAD v2.1 allele frequency is 7.96388e-06 (2/251134 alleles), and the gnomAD v4.1 allele frequency is 2.47815e-06 (4/1614108 alleles), both below the 0.1% PM2 threshold.

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 supporting; combination = 1 very strong + 1 supporting, 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

4 / 1,614,108 alleles

gnomAD v4.1: 4 / 1,614,108 alleles. Recorded AF 2.47815e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.96388e-06; MAF= 0.00080%, 2/251134 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 4.62022e-05; MAF= 0.00462%, 1/21644 alleles, homozygotes = 0).

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗

SpliceAI score

0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. 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

16 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV105020525, n = 16 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: 2 met · 4 not met · 15 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

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

Met Not met Not assessed Not applicable

The TET2 c.2926C>T (p.Gln976Ter; p.Q976*) variant has been reported in curated somatic cancer resources and has not been reported in ClinVar.

This variant is present at very low frequency in population databases, with allele frequency 7.96388e-06 in gnomAD v2.1 and 2.47815e-06 in gnomAD v4.1, both below the PM2 threshold.

Available gene-level studies support TET2 loss-of-function biology and structural importance of the C-terminal catalytic region, but no variant-specific functional assay for p.(Gln976Ter) was identified.

Computational review showed no significant predicted splice effect by SpliceAI, with a maximum delta score of 0.01; REVEL was unavailable, and BayesDel score 0.294732 did not provide sufficient support for PP3 or BP4 for this nonsense variant.

Met · 2

PVS1 Very strongThis variant is a nonsense change, p.(Gln976Ter), in TET2. Available gene-level evidence supports loss of function as a germline disease mechanism for TET2, and the generic PVS1 framework is eligible. The premature stop occurs well upstream of the terminal exon structure for this transcript, supporting a loss-of-function effect rather than a tolerated distal truncation. Details ▾Hide ▴

Rule

Generic ClinGen SVI PVS1 framework

Evidence considered

Nonsense variant p.(Gln976Ter) / p.(Q976*)
Generic PVS1 fallback was marked applicable
TET2 loss of function was supported as a germline disease mechanism

Still missing

No official gene-specific PVS1 framework was available.

Sources

pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗

PM2 SupportingThis variant is present at very low frequency in population databases. The gnomAD v2.1 allele frequency is 7.96388e-06 (2/251134 alleles), and the gnomAD v4.1 allele frequency is 2.47815e-06 (4/1614108 alleles), both below the 0.1% PM2 threshold. Details ▾Hide ▴

Rule

Population frequency below PM2 threshold

Evidence considered

gnomAD v2.1 AF 7.96388e-06
gnomAD v4.1 AF 2.47815e-06
No homozygotes observed

Sources

gnomad_v2 ↗gnomad_v4 ↗

Not met · 4 · evaluated, threshold not reached

PP3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01. REVEL was unavailable, and BayesDel score 0.294732 does not provide a validated basis to apply PP3 for this nonsense variant. Available computational evidence therefore does not support PP3. Details ▾Hide ▴

Evidence considered

SpliceAI max delta 0.01
REVEL not available
BayesDel score 0.294732

Still missing

No validated variant-specific computational framework supporting PP3 for this nonsense change was identified.

Sources

spliceai ↗bayesdel

BA1 Population frequency does not meet BA1. The highest observed gnomAD v4.1 allele frequency is 2.47815e-06 overall, which is far below the 1% BA1 threshold. Details ▾Hide ▴

Rule

BA1 threshold >1%

Evidence considered

gnomAD v4.1 AF 2.47815e-06

Sources

gnomad_v4 ↗

BS1 Population frequency does not meet BS1. The highest observed population frequency is 4.62022e-05 in gnomAD v2.1 Finnish samples, which is below the 0.3% BS1 threshold. Details ▾Hide ▴

Rule

BS1 threshold >0.3%

Evidence considered

gnomAD v2.1 Finnish AF 4.62022e-05
gnomAD v4.1 Finnish AF 1.56172e-05

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP4 Computational evidence does not support a benign interpretation. Although SpliceAI shows no significant splice effect with a maximum delta score of 0.01, this is a nonsense variant and there is no broader computational evidence sufficient to support BP4. Details ▾Hide ▴

Evidence considered

SpliceAI max delta 0.01
BayesDel score 0.294732
REVEL unavailable

Still missing

No validated benign computational framework for this nonsense change was identified.

Sources

spliceai ↗bayesdel

Not assessed · 15 · no assessment recorded

PS1 No evidence was identified for a different nucleotide change producing the same amino acid consequence with an established pathogenic classification, so PS1 could not be assessed. Details ▾Hide ▴

Evidence considered

ClinVar search found no record for this variant

Still missing

No same-amino-acid comparator assertion was identified.

Sources

clinvar ↗

PS2 No confirmed de novo occurrence with parental confirmation was identified for this variant, so PS2 was not met. Details ▾Hide ▴

Evidence considered

No ClinVar record
No de novo evidence identified in exploratory review

Still missing

No maternity/paternity-confirmed de novo report was identified.

Sources

clinvar ↗

PS3 Published TET2 studies describe gene-level functional and structural effects relevant to loss of function, but no variant-specific well-established functional assay result for p.(Gln976Ter) was identified. Available evidence therefore does not support applying PS3. Details ▾Hide ▴

Evidence considered

Gene-level functional literature was identified
No direct assay result for this exact variant was provided

Still missing

No variant-specific functional assay for p.(Gln976Ter) was identified.

Sources

PMID:21057493 ↗PMID:24315485 ↗oncokb ↗

PS4 This variant has not been reported in ClinVar, and no affected-case enrichment data for germline disease were identified. Somatic observations alone do not establish PS4 for germline interpretation. Details ▾Hide ▴

Evidence considered

ClinVar absent
Curated somatic resource context exists but does not establish germline enrichment

Still missing

No germline case-control or affected-case enrichment data were identified.

Sources

clinvar ↗oncokb ↗

PM3 No data were identified showing this variant in trans with another pathogenic variant in a recessive disease context, so PM3 could not be assessed. Details ▾Hide ▴

Still missing

No phase data or recessive case observations were identified.

PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant, so PM6 was not met. Details ▾Hide ▴

Evidence considered

No ClinVar record
No PM6-style family data identified

Still missing

No de novo report without full parental confirmation was identified.

Sources

clinvar ↗

PP1 No segregation data were identified for this variant, so PP1 could not be applied. Details ▾Hide ▴

Evidence considered

No ClinVar record
No segregation evidence identified

Still missing

No family segregation report was identified.

Sources

clinvar ↗

PP4 No phenotype-specific clinical data were provided that would establish a highly specific TET2-related presentation for this individual, so PP4 could not be assessed. Details ▾Hide ▴

Still missing

No case phenotype details were available for phenotype specificity review.

PP5 This variant is absent from ClinVar, and no germline reputable-source pathogenic assertion suitable for PP5 was identified. Details ▾Hide ▴

Evidence considered

Variant absent from ClinVar

Still missing

No germline reputable-source pathogenic assertion was identified.

Sources

clinvar ↗

BS2 No evidence was identified showing this variant in healthy adult individuals at a level sufficient to apply BS2. Details ▾Hide ▴

Still missing

No healthy adult carrier data appropriate for BS2 were identified.

BS3 Available studies provide gene-level functional and structural context for TET2, but no well-established variant-specific assay showing normal function for p.(Gln976Ter) was identified. BS3 was therefore not applied. Details ▾Hide ▴

Evidence considered

Gene-level functional literature was identified
No benign functional assay result for this exact variant was provided

Still missing

No variant-specific normal-function assay was identified.

Sources

PMID:21057493 ↗PMID:24315485 ↗oncokb ↗

BS4 No non-segregation data were identified for this variant, so BS4 could not be assessed. Details ▾Hide ▴

Evidence considered

No ClinVar record
No family non-segregation data identified

Still missing

No unaffected carrier or non-segregation evidence was identified.

Sources

clinvar ↗

BP2 No phase data were identified showing this variant in cis with a pathogenic variant or in trans with a pathogenic variant in a dominant condition, so BP2 could not be assessed. Details ▾Hide ▴

Still missing

No phase information was identified.

BP5 No alternate molecular cause explaining the phenotype was identified, so BP5 could not be assessed. Details ▾Hide ▴

Still missing

No phenotype-specific alternative diagnosis data were available.

BP6 This variant is absent from ClinVar, and no germline reputable-source benign assertion suitable for BP6 was identified. Details ▾Hide ▴

Evidence considered

Variant absent from ClinVar

Still missing

No germline reputable-source benign assertion was identified.

Sources

clinvar ↗

Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴

PM1 N/APM1 is not applied here because this is a truncating variant rather than a missense change at a defined critical residue, and the residue is not shown to lie in a statistically significant hotspot. Details ▾Hide ▴

Evidence considered

No statistically significant hotspot at Q976
Available structural literature is gene-level rather than variant-specific hotspot evidence

Sources

hotspots ↗PMID:24315485 ↗

PM4 N/APM4 is not applicable because this variant is a nonsense substitution, not a protein length change caused by an in-frame indel or stop-loss variant. Details ▾Hide ▴

Evidence considered

Variant consequence is nonsense

PM5 N/APM5 was not applied because classic same-residue PM5 semantics could not be confirmed for this framework, and no same-residue pathogenic comparator variants were established. Details ▾Hide ▴

Evidence considered

PM5 candidate review marked classic PM5 search as not eligible

Sources

pm5_candidates

PP2 N/APP2 is not applicable because this variant is not a missense change. Details ▾Hide ▴

Evidence considered

Variant consequence is nonsense

BP1 N/ABP1 is not applicable because this variant is not a missense change, and available TET2 evidence supports loss of function rather than a predominantly benign truncating mechanism. Details ▾Hide ▴

Evidence considered

Variant consequence is nonsense
TET2 loss of function is supported

Sources

pvs1_gene_context

BP3 N/ABP3 is not applicable because this variant is not an in-frame deletion or insertion in a repetitive region. Details ▾Hide ▴

Evidence considered

Variant consequence is nonsense substitution

BP7 N/ABP7 is not applicable because this variant is a nonsense coding change, not a synonymous or deep intronic variant. Details ▾Hide ▴

Evidence considered

Variant consequence is nonsense

Identifiers

Gene: TET2
Transcript: NM_001127208.2
Coding (HGVS c.): NM_001127208.2:c.2926C>T
Protein (HGVS p.): NP_001120680.1:p.(Gln976Ter)
GRCh38: chr4:105236868 C>T
GRCh37: chr4:106158025 C>T
COSMIC: COSV105020525

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 4 / 1,614,108 alleles AF 2.48e-06 · 0 homozygotes · FAF 6.8e-07

gnomAD v2.1 2 / 251,134 alleles AF 7.96e-06 · 0 homozygotes

By genetic ancestry

gnomAD v4.1

AF 2.5e-06 · 4 / 1,614,108 alleles · 0 hom · FAF 6.8e-07

European (Finnish)1 / 64,032	1.6e-05
European (non-Finnish)3 / 1,180,002	2.5e-06

0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 8e-06 · 2 / 251,134 alleles · 0 hom

European (Finnish)1 / 21,644	4.6e-05
European (non-Finnish)1 / 113,524	8.8e-06

0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 2.47815e-06; MAF= 0.00025%, 4/1614108 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 1.56172e-05; MAF= 0.00156%, 1/64032 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

gnomAD v2.1

SpliceAI and Pangolin

SpliceAI acceptor lossat -51 bp

0.000

SpliceAI acceptor gainat -283 bp

0.010

SpliceAI donor lossat +483 bp

0.010

SpliceAI donor gainat -173 bp

0.010

Pangolin splice lossmagnitude shown

-0.030

Pangolin splice gain

0.060

Other predictors

REVEL: Not available
BayesDel: 0.295

How the predictions were used

Evidence considered

SpliceAI max delta 0.01
REVEL not available
BayesDel score 0.294732

Still missing

No validated variant-specific computational framework supporting PP3 for this nonsense change was identified.

Sources

spliceai ↗bayesdel

Evidence considered

SpliceAI max delta 0.01
BayesDel score 0.294732
REVEL unavailable

Still missing

No validated benign computational framework for this nonsense change was identified.

Sources

spliceai ↗bayesdel

BP7 N/ABP7 is not applicable because this variant is a nonsense coding change, not a synonymous or deep intronic variant. Details ▾Hide ▴

Evidence considered

Variant consequence is nonsense

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.294732.

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 4 / 1,614,108 recorded alleles Open source ↗

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

SpliceAI Lookup Recorded maximum delta 0.010 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

gnomAD v2.1

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.294732.

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; COSV105020525, n = 16 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.