TET2c.4139A>CLikely benign

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Variant interpretation report

TET2 c.4139A>C, p.(His1380Pro)

NM_001127208.2:c.4139A>C NP_001120680.1:p.(His1380Pro) View identifiers

Classification

Likely benign

Variant description:

No variant summary was recorded for this case.

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

Likely benign.A likely benign 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: 2 supporting (benign) · 1 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 25 Jun 2026 · version 7.0.0

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): This variant is absent from all population databases, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Complete absence from large population cohorts supports a rare variant consistent with potential pathogenicity.
BP1 (supporting): TET2 loss-of-function (truncating) variants are an established germline disease mechanism, associated with an autoimmune lymphoproliferative syndrome-like phenotype and hematologic malignancies (PMID:36066697, PMID:40031954). This variant is a missense substitution (p.His1380Pro) in a gene where primarily truncating variants are known to cause disease.
BP4 (supporting): Multiple lines of computational evidence suggest no significant impact on the gene product. BayesDel score is 0.120 (predicting benign). SpliceAI max delta score is 0.00 (no predicted splicing alteration). Although REVEL score is 0.657 (intermediate), two independent in silico methods converge on a benign or neutral prediction.

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: 2

Pathogenic criteria applied · 1

PM2Supporting

PM2 · supporting

This variant is absent from all population databases, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Complete absence from large population cohorts supports a rare variant consistent with potential pathogenicity.

Benign criteria applied · 2

BP1Supporting

BP1 · supporting

TET2 loss-of-function (truncating) variants are an established germline disease mechanism, associated with an autoimmune lymphoproliferative syndrome-like phenotype and hematologic malignancies (PMID:36066697, PMID:40031954). This variant is a missense substitution (p.His1380Pro) in a gene where primarily truncating variants are known to cause disease.

BP4Supporting

BP4 · supporting

Multiple lines of computational evidence suggest no significant impact on the gene product. BayesDel score is 0.120 (predicting benign). SpliceAI max delta score is 0.00 (no predicted splicing alteration). Although REVEL score is 0.657 (intermediate), two independent in silico methods converge on a benign or neutral prediction.

Recorded classification: Likely benign

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 supporting, BP1 supporting benign, BP4 supporting benign; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.

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

0.000 maximum delta

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

Applied · BP4 → SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TET2, a tumor suppressor and DNA demethylase, is frequently mutated in hematologic malignancies.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

4 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV54423180, 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.

29 criteria with recorded statuses: 3 met · 8 not met · 12 not assessed · 6 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

Variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases, meeting PM2 at supporting strength.

TET2 loss-of-function variants are an established germline disease mechanism; this missense variant (p.His1380Pro) occurs in a gene where truncating variants are the primary known cause of disease, meeting BP1 at supporting strength.

Multiple computational tools predict no significant impact: BayesDel score 0.120 (benign) and SpliceAI max delta 0.00 (no splicing alteration), meeting BP4 at supporting strength.

REVEL score of 0.657 is intermediate and does not qualify for PP3; no other pathogenic criteria are met. Overall classification: Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules (PM2_supporting + BP1_supporting + BP4_supporting).

Met · 3

PM2 SupportingThis variant is absent from all population databases, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Complete absence from large population cohorts supports a rare variant consistent with potential pathogenicity. Details ▾Hide ▴

Evidence considered

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

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BP1 SupportingTET2 loss-of-function (truncating) variants are an established germline disease mechanism, associated with an autoimmune lymphoproliferative syndrome-like phenotype and hematologic malignancies (PMID:36066697, PMID:40031954). This variant is a missense substitution (p.His1380Pro) in a gene where primarily truncating variants are known to cause disease. Details ▾Hide ▴

Evidence considered

TET2 LOF mechanism supported by germline literature (PMID:36066697
PMID:40031954)
Truncating variants are established disease mechanism in TET2-related ALPS-like phenotype
Current variant is a missense change (H1380P)
not a truncating variant

Sources

pvs1_gene_context

BP4 SupportingMultiple lines of computational evidence suggest no significant impact on the gene product. BayesDel score is 0.120 (predicting benign). SpliceAI max delta score is 0.00 (no predicted splicing alteration). Although REVEL score is 0.657 (intermediate), two independent in silico methods converge on a benign or neutral prediction. Details ▾Hide ▴

Evidence considered

BayesDel: 0.120 (benign-predicting)
SpliceAI: max delta 0.00 (no splicing impact)
REVEL: 0.657 (intermediate
does not negate benign predictions)

Sources

bayesdelspliceai ↗revel

Not met · 8 · evaluated, threshold not reached

PS1 No prior report of a pathogenic variant resulting in the same amino acid change (p.His1380Pro) was identified. The variant is absent from ClinVar and no literature reports this specific amino acid substitution as pathogenic. Details ▾Hide ▴

Evidence considered

Variant absent from ClinVar
no variation ID found
No literature reports of p.His1380Pro as a pathogenic change

Sources

clinvar ↗

PM1 This variant does not lie within a statistically significant mutational hotspot in TET2. Details ▾Hide ▴

Evidence considered

Cancer Hotspots analysis: residue not significant
exact variant not listed

PP3 Multiple in silico tools do not converge on a deleterious prediction. REVEL score is 0.657 (intermediate, below the 0.75 threshold for pathogenic prediction). BayesDel score is 0.120 (predicting benign). SpliceAI max delta score is 0.00 (no predicted splicing impact). The in silico evidence does not meet the threshold for multiple lines supporting a deleterious effect. Details ▾Hide ▴

Evidence considered

REVEL: 0.657 (intermediate
below 0.75 pathogenic threshold)
BayesDel: 0.120 (benign-predicting)
SpliceAI: max delta 0.00 (no splicing impact)

Sources

revelbayesdelspliceai ↗

PP5 This variant is absent from ClinVar and has not been classified by any reputable source or expert panel. Details ▾Hide ▴

Evidence considered

Variant absent from ClinVar
no classification by any submitter

Sources

clinvar ↗

BA1 BA1 requires an allele frequency above 1% in population databases. This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0.0). Details ▾Hide ▴

Evidence considered

Variant absent from all population databases
allele frequency 0.0

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS1 BS1 requires an allele frequency above 0.3% in population databases. This variant is absent from all gnomAD cohorts (allele frequency 0.0). Details ▾Hide ▴

Evidence considered

Variant absent from all population databases
allele frequency 0.0

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BP6 This variant is absent from ClinVar and has not been classified as benign by any reputable source. Details ▾Hide ▴

Evidence considered

Variant absent from ClinVar
no benign classification from any submitter

Sources

clinvar ↗

PS5 No alternate pathogenic missense variant identified at amino acid residue His1380. PM5 candidate harvesting found no comparator variants at this position. Details ▾Hide ▴

Evidence considered

PM5 candidate search: 0 same-residue candidates found
No ClinVar pathogenic variants reported at residue 1380

Sources

pm5_candidates

Not assessed · 12 · no assessment recorded

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

Still missing

No parental testing or de novo reports available

PS3 No variant-specific functional studies identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' and provides no reviewed functional evidence. COSMIC reports somatic occurrence (COSV54423180, n=4) but no functional characterization. Details ▾Hide ▴

Evidence considered

OncoKB: Unknown Oncogenic Effect
no variant-specific functional evidence
COSMIC: COSV54423180
somatic count 4
no functional annotation

Still missing

No in vitro or in vivo functional studies available

Sources

oncokb ↗

PS4 No case-control or prevalence data available to assess enrichment of this variant in affected individuals versus controls. Details ▾Hide ▴

Still missing

No case-control studies or variant-specific prevalence data

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

Still missing

No de novo reports available

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

Still missing

No family studies or cosegregation analysis

PP2 HCI prior data are not available for TET2; the rate of benign missense variation in this gene cannot be assessed. PP2 requires demonstration that the gene has a low rate of benign missense variation and that missense variants are a common disease mechanism. Details ▾Hide ▴

Evidence considered

HCI prior lookup: gene TET2 not supported
no HCI probability score available

Still missing

No HCI prior data to assess benign missense constraint

PP4 No patient-specific phenotypic data available to assess whether this variant is found in a patient with a phenotype highly specific for TET2-related disease. Details ▾Hide ▴

Still missing

No patient phenotype data available

BS2 No data on observation of this variant in healthy adults with full penetrance expected. Details ▾Hide ▴

Still missing

No observation data in healthy adult controls

BS3 No variant-specific functional studies demonstrating no damaging effect on protein function or splicing. Details ▾Hide ▴

Still missing

No functional studies available

BS4 No segregation data available to assess lack of cosegregation with disease. Details ▾Hide ▴

Still missing

No family segregation data

BP2 No data on observation of this variant in trans with a known pathogenic variant in a recessive disorder. Details ▾Hide ▴

Still missing

No genotype data for in trans assessment

BP5 No data on an alternate molecular basis for disease that would rule out this variant as causative. Details ▾Hide ▴

Still missing

No alternate molecular diagnosis data

Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/APVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice consensus). This variant is a missense substitution (c.4139A>C, p.His1380Pro) and does not fall into any PVS1 null-variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴

Evidence considered

Variant classified as missense (H1380P) by Mutalyzer and VariantValidator
variant_bucket: other
apply_generic_pvs1_framework: false per PVS1 variant assessment

Sources

pvs1_variant_assessmentpvs1_generic_framework ↗

PM3 N/APM3 requires observation of the variant in trans with a known pathogenic variant for recessive disorders. No such data available and TET2 is not established as a recessive disease gene. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein length changes caused by in-frame insertions/deletions or stop-loss variants. This variant is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo pathogenic missense comparator variants identified at the same amino acid residue (His1380) in ClinVar. PM5 candidate harvesting returned no same-residue candidates for comparison. Details ▾Hide ▴

Evidence considered

PM5 candidate search yielded 0 same-residue candidates
Pipeline recommendation: not_applicable

Sources

pm5_candidates

BP3 N/ABP3 applies to in-frame insertions or deletions in repetitive regions. This variant is a single nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies only to synonymous variants with no predicted splicing impact. This variant is a missense substitution (c.4139A>C, p.His1380Pro). Details ▾Hide ▴

Evidence considered

Variant is missense (His1380Pro)
not synonymous

Identifiers

Gene: TET2
Transcript: NM_001127208.2
Coding (HGVS c.): NM_001127208.2:c.4139A>C
Protein (HGVS p.): NP_001120680.1:p.(His1380Pro)
GRCh38: chr4:105269704 A>C
GRCh37: chr4:106190861 A>C
COSMIC: COSV54423180

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 +29 bp

0.000

SpliceAI acceptor gainat -94 bp

0.000

SpliceAI donor lossat +233 bp

0.000

SpliceAI donor gainat +43 bp

0.000

Pangolin splice lossmagnitude shown

-0.000

Pangolin splice gain

0.010

Other predictors

REVEL: 0.657
BayesDel: 0.120

How the predictions were used

Evidence considered

BayesDel: 0.120 (benign-predicting)
SpliceAI: max delta 0.00 (no splicing impact)
REVEL: 0.657 (intermediate
does not negate benign predictions)

Sources

bayesdelspliceai ↗revel

Evidence considered

REVEL: 0.657 (intermediate
below 0.75 pathogenic threshold)
BayesDel: 0.120 (benign-predicting)
SpliceAI: max delta 0.00 (no splicing impact)

Sources

revelbayesdelspliceai ↗

BP7 N/ABP7 applies only to synonymous variants with no predicted splicing impact. This variant is a missense substitution (c.4139A>C, p.His1380Pro). Details ▾Hide ▴

Evidence considered

Variant is missense (His1380Pro)
not synonymous

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.657. BayesDel score = 0.120127.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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 0.000 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

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 = 0.00). REVEL score = 0.657. BayesDel score = 0.120127.

Functional

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54423180, n = 4 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.