TET2c.2814_2815delUncertain significance

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Variant interpretation report

TET2 c.2814_2815del, p.(Gln939AspfsTer32)

NM_001127208.2:c.2814_2815del NP_001120680.1:p.(Gln939AspfsTer32) 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.

Key facts

Evidence used: 1 very strong (pathogenic) · 1 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 20 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): NM_001127208.2:c.2814_2815del is a frameshift variant predicted to result in a premature termination codon at residue 970 (p.Gln939AspfsTer32) in exon 3 of 11 exons, well upstream of the last exon-exon junction, and is predicted to trigger nonsense-mediated decay. TET2 loss of function is established as a germline disease mechanism for an autoimmune lymphoproliferative syndrome-like phenotype with hematologic malignancy. Under the ClinGen SVI PVS1 framework (PMC6185798), this frameshift variant qualifies for PVS1 at very strong strength.
PM2 (supporting): This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, consistent with PM2 under generic ACMG/AMP criteria (allele frequency <0.1% in all populations).

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.2814_2815del is a frameshift variant predicted to result in a premature termination codon at residue 970 (p.Gln939AspfsTer32) in exon 3 of 11 exons, well upstream of the last exon-exon junction, and is predicted to trigger nonsense-mediated decay. TET2 loss of function is established as a germline disease mechanism for an autoimmune lymphoproliferative syndrome-like phenotype with hematologic malignancy. Under the ClinGen SVI PVS1 framework (PMC6185798), this frameshift variant qualifies for PVS1 at very strong strength.

PM2Supporting

PM2 · supporting

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, consistent with PM2 under generic ACMG/AMP criteria (allele frequency <0.1% in all populations).

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.

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

0.060 maximum delta

Recorded SpliceAI maximum delta score: 0.060. 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.

29 criteria with recorded statuses: 2 met · 5 not met · 11 not assessed · 11 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 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.2814_2815del (p.Gln939AspfsTer32) is a frameshift deletion in exon 3 of TET2 predicted to introduce a premature termination codon at residue 970, triggering nonsense-mediated decay. Under the ClinGen SVI generic PVS1 framework (PMC6185798), this qualifies for PVS1 at very strong strength, as TET2 loss of function is an established germline disease mechanism for autoimmune lymphoproliferative syndrome-like phenotype with hematologic malignancy.

This variant is absent from all queried population databases (gnomAD v2.1, v4.1, gnomAD-Canada), consistent with PM2 at supporting strength.

The variant is absent from ClinVar and has no variant-specific functional studies, case-control data, or segregation data in the literature. Two papers (PMID:21057493, PMID:24315485) characterize TET2 catalytic function and structure but do not mention this specific variant.

Met · 2

PVS1 Very strongNM_001127208.2:c.2814_2815del is a frameshift variant predicted to result in a premature termination codon at residue 970 (p.Gln939AspfsTer32) in exon 3 of 11 exons, well upstream of the last exon-exon junction, and is predicted to trigger nonsense-mediated decay. TET2 loss of function is established as a germline disease mechanism for an autoimmune lymphoproliferative syndrome-like phenotype with hematologic malignancy. Under the ClinGen SVI PVS1 framework (PMC6185798), this frameshift variant qualifies for PVS1 at very strong strength. Details ▾Hide ▴

Evidence considered

Frameshift variant p.Gln939AspfsTer32 in exon 3/11 with PTC at codon 970
predicted to trigger NMD per PMC6185798 criteria
TET2 germline loss-of-function established as disease mechanism for ALPS-like phenotype and hematologic malignancy (PMID:36066697
PMID:40031954)

Sources

pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment

PM2 SupportingThis variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, consistent with PM2 under generic ACMG/AMP criteria (allele frequency <0.1% in all populations). Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (0 alleles)
Absent from gnomAD v4.1 (0 alleles)
Absent from gnomAD-Canada v1.0 (0 alleles)

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 5 · evaluated, threshold not reached

PM1 This variant is located in exon 3, encoding the N-terminal region of TET2 (codon 939 of 2003), upstream of the well-characterized C-terminal catalytic domain (Cys-rich and DSBH domains, approximately residues 1129-1936). Hotspot analysis confirms no statistically significant mutational hotspot at this position. Details ▾Hide ▴

Evidence considered

Residue 939 lies in N-terminal region
not in the catalytic DSBH or Cys-rich domains defined by PMID:24315485
Cancer Hotspots database confirms no statistically significant hotspot at this residue

PP3 SpliceAI predicts no significant splice impact (max delta score 0.06, well below the 0.2 threshold). REVEL and BayesDel scores are not available for this deletion variant. No computational evidence supports a deleterious effect. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score = 0.06 (no predicted splice alteration)
REVEL and BayesDel not applicable (not an SNV)

Sources

spliceai ↗

BA1 This variant is absent from gnomAD population databases; allele frequency is 0%, far below the BA1 threshold of >5%. Details ▾Hide ▴

Evidence considered

Allele frequency 0% in gnomAD v2.1 and v4.1

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 This variant is absent from gnomAD; allele frequency is 0%, below the BS1 threshold of >0.3% for non-VCEP assessment. Details ▾Hide ▴

Evidence considered

Allele frequency 0% in gnomAD v2.1 and v4.1

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP4 SpliceAI predicts no splice impact (max delta 0.06), but REVEL and BayesDel scores are not available for this deletion. A single benign computational prediction is insufficient to meet BP4, which requires multiple lines of computational evidence suggesting no impact. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.06 (no predicted splice alteration)

Sources

spliceai ↗

Not assessed · 11 · no assessment recorded

PS2 No de novo data are available for this variant. Details ▾Hide ▴

Still missing

Absence of parental testing or de novo confirmation

PS3 No variant-specific functional studies were identified. The available literature (PMID:21057493, PMID:24315485) discusses TET2 catalytic function and missense mutations in myeloid malignancies but does not include NM_001127208.2:c.2814_2815delTC. Details ▾Hide ▴

Still missing

No functional data for this specific variant

PS4 No case-control or prevalence data are available for this variant. Details ▾Hide ▴

Still missing

No affected vs. control prevalence data

PM6 No de novo data are available for this variant. Details ▾Hide ▴

Still missing

No de novo confirmation with parental testing

PP1 No segregation data are available for this variant. Details ▾Hide ▴

Still missing

No family segregation data

PP4 No patient-specific phenotype data are available for this variant. Details ▾Hide ▴

Still missing

No patient phenotype information provided

BS2 No data are available on observation of this variant in healthy adults. Details ▾Hide ▴

Still missing

No data on observation in healthy adult controls

BS3 No variant-specific functional studies demonstrating no deleterious effect were identified. The available literature (PMID:21057493, PMID:24315485) addresses TET2 general function and missense mutations but does not include this frameshift variant. Details ▾Hide ▴

Still missing

No functional studies for this variant showing benign effect

BS4 No segregation data are available for this variant. Details ▾Hide ▴

Still missing

No family segregation data to assess lack of cosegregation

BP2 No data are available on observation of this variant in trans with a pathogenic variant. Details ▾Hide ▴

Still missing

No trans-phase data with known pathogenic variants

BP5 No data are available on observation of this variant in a case with an alternate molecular cause. Details ▾Hide ▴

Still missing

No alternate molecular diagnosis identified

Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/AThis is a frameshift deletion, not a nucleotide substitution with a known pathogenic alternate at the same position. Details ▾Hide ▴

No further detail was recorded.

PM3 N/ASkipped: PM3 applies to recessive disorders; TET2-related germline disease follows autosomal dominant/heterozygous LoF mechanism. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AThis frameshift variant is already assessed under PVS1. Applying PM4 would constitute double-counting of the same protein-truncation evidence per ACMG/AMP 2015 guidance. Details ▾Hide ▴

No further detail was recorded.

PM5 N/AThis is a frameshift variant. PM5 applies to novel missense variants at a residue where a different pathogenic missense change has been established; no same-residue missense comparator is applicable. 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 variant. Details ▾Hide ▴

No further detail was recorded.

PP5 N/AThis variant is absent from ClinVar and has not been classified as pathogenic by any expert panel or reputable source. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where only truncating variants cause disease. This is a truncating (frameshift) variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions. This is a frameshift deletion, not an in-frame variant. Details ▾Hide ▴

No further detail was recorded.

BP6 N/AThis variant is absent from ClinVar; no reputable source has classified it as benign. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to silent (synonymous) variants with no predicted splice impact. This is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

PS5 N/AThis variant is absent from ClinVar and no expert panel or reputable source has classified it as pathogenic. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: TET2
Transcript: NM_001127208.2
Coding (HGVS c.): NM_001127208.2:c.2814_2815del
Protein (HGVS p.): NP_001120680.1:p.(Gln939AspfsTer32)
GRCh38: chr4:105236754 ACT>A
GRCh37: chr4:106157911 ACT>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 -169 bp

0.060

SpliceAI acceptor gainat +63 bp

0.010

SpliceAI donor lossat -59 bp

0.040

SpliceAI donor gainat +203 bp

0.010

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 = 0.06 (no predicted splice alteration)
REVEL and BayesDel not applicable (not an SNV)

Sources

spliceai ↗

Evidence considered

SpliceAI max delta = 0.06 (no predicted splice alteration)

Sources

spliceai ↗

BP7 N/ABP7 applies to silent (synonymous) variants with no predicted splice impact. This is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).

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.

Demonstrated that somatic TET2 missense mutations (H1302Y, D1304A, H1802R/Q, W1211R, P1287S, C1834D, R1817S/M) impair catalytic hydroxylation of 5-methylcytosine to 5-hydroxymethylcytosine, and that TET2-mutant bone marrow samples from myeloid malignancy patients display uniformly low 5-hmC levels. NM_001127208.2:c.2814_2815delTC 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 A resolution, defining the Cys-rich and DSBH domain architecture and the Fe2+/2OG coordination within the active site. NM_001127208.2:c.2814_2815delTC was not identified in the available abstract.
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 0.060 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 = 0.06).

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.