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TET2c.5651C>AUncertain significance
Print report
Variant interpretation report

TET2 c.5651C>A, p.(Thr1884Asn)

NM_001127208.2:c.5651C>A NP_001120680.1:p.(Thr1884Asn) 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: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

NM_001127208.2:c.5651C>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (0/1,551,598 alleles; AF=0%), and gnomAD-Canada v1.0, meeting the PM2 threshold of <0.1% under the generic ACMG/AMP framework.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence predict no damaging effect. BayesDel score is -0.27313 (benign prediction), REVEL score is 0.302 (neutral, below pathogenicity threshold), and SpliceAI predicts no splice impact (max delta = 0.00).

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: PM2 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, 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
0.000 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
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV54403709, n = 1 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: 2 met · 6 not met · 13 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_001127208.2:c.5651C>A (p.Thr1884Asn) is a missense variant in TET2, a gene with emerging germline disease association involving autoimmune lymphoproliferative syndrome-like phenotypes and hematologic malignancy.

The variant is absent from gnomAD v2.1 and v4.1 (0/1,551,598 alleles) and gnomAD-Canada, meeting PM2 at moderate strength.

Multiple in silico tools predict a neutral or benign effect: BayesDel score is -0.27313 (benign), REVEL score is 0.302 (neutral), and SpliceAI delta is 0.00 (no splice impact), meeting BP4 at supporting benign strength.

The variant is absent from ClinVar and has not been classified by any expert panel. OncoKB reports an 'Unknown Oncogenic Effect' with no variant-specific functional evidence.

One somatic observation exists in COSMIC (COSV54403709, n=1), but this does not independently support germline pathogenicity.

No functional studies, family segregation data, de novo observations, or case-control data are available. Literature search returned zero variant-specific PMIDs.

With one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), this variant does not meet the threshold for Likely Pathogenic (requires ≥2 moderate or ≥1 moderate + ≥4 supporting) or Likely Benign (requires ≥1 strong benign + ≥1 supporting benign, or ≥2 supporting benign). The variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 rules.

Met · 2

PM2 ModerateNM_001127208.2:c.5651C>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (0/1,551,598 alleles; AF=0%), and gnomAD-Canada v1.0, meeting the PM2 threshold of <0.1% under the generic ACMG/AMP framework. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1 (0 alleles / 1
  • 551
  • 598 total
  • AF=0.0%)
  • Absent from gnomAD-Canada v1.0
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence predict no damaging effect. BayesDel score is -0.27313 (benign prediction), REVEL score is 0.302 (neutral, below pathogenicity threshold), and SpliceAI predicts no splice impact (max delta = 0.00). Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.27313 (benign prediction)
  • REVEL: 0.302 (neutral
  • below 0.5 pathogenicity threshold)
  • SpliceAI: max delta 0.00 (no splice impact)
Sources
revelbayesdelspliceai ↗

Not met · 6 · evaluated, threshold not reached

PM1 This variant does not reside in a statistically significant mutational hotspot as determined by Cancer Hotspots analysis. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: variant not located in a statistically significant hotspot
PP3 Multiple in silico tools do not support a deleterious effect. REVEL score is 0.302 (below the typical pathogenicity threshold of 0.5), BayesDel score is -0.27313 (predicting benign), and SpliceAI predicts no splice impact (max delta = 0.00). Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.302 (neutral
  • below 0.5 pathogenicity threshold)
  • BayesDel score: -0.27313 (benign prediction)
  • SpliceAI max delta: 0.00 (no splice impact predicted)
Sources
revelbayesdelspliceai ↗
PP5 No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar, and OncoKB reports an 'Unknown Oncogenic Effect.' Details ▾Hide ▴
Evidence considered
  • ClinVar: variant not present
  • no classifications available
  • OncoKB: Unknown Oncogenic Effect
Sources
clinvar ↗oncokb ↗
BA1 The variant is absent from gnomAD v4.1 (0/1,551,598 alleles; AF=0%), well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF=0.0% (0/1
  • 551
  • 598 alleles)
Sources
gnomad_v4 ↗
BS1 The variant is absent from gnomAD v4.1 (0/1,551,598 alleles; AF=0%), well below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF=0.0% (0/1
  • 551
  • 598 alleles)
Sources
gnomad_v4 ↗
BP6 No reputable source has classified this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • ClinVar: variant not present
  • no benign classifications available
Sources
clinvar ↗

Not assessed · 13 · no assessment recorded

PS3 No well-established functional studies are available for NM_001127208.2:c.5651C>A. Literature search returned zero PMIDs, and OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific curated functional evidence. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no variant-specific functional studies curated
  • No PMIDs identified in literature_pass for this variant
Still missing
  • No functional assay data exist for this variant
Sources
oncokb ↗
PS4 No case-control or prevalence data are available to assess whether this variant is statistically enriched in affected individuals. Details ▾Hide ▴
Still missing
  • No case-control studies or cohort prevalence data available
PM6 No de novo observation data are available for this variant. The variant is absent from ClinVar and no publications report a de novo occurrence. Details ▾Hide ▴
Still missing
  • No de novo testing or trio data available
PP1 No family segregation data are available for this variant. Details ▾Hide ▴
Still missing
  • No family studies or co-segregation data available
PP2 Insufficient data are available to determine whether TET2 has a low rate of benign missense variation and whether missense variants are a common mechanism of disease. TET2 germline disease context is recognized, but gene-level missense constraint metrics (e.g., Z-score) are not available for this assessment. Details ▾Hide ▴
Evidence considered
  • TET2 germline disease context is supported by literature (PMID:36066697
  • PMID:40031954) but missense constraint data are not available
Still missing
  • No gene-level missense constraint metrics (Z-score
  • gnomAD constraint) available
PP4 No patient phenotype or family history data are available to determine whether the clinical presentation is highly specific for a TET2-related disorder. Details ▾Hide ▴
Still missing
  • No proband phenotype or clinical data available
BS2 No data are available regarding observation of this variant in healthy adults where full penetrance would be expected at an early age. Details ▾Hide ▴
Still missing
  • No healthy adult observational data available
BS3 No well-established functional studies are available to demonstrate a lack of damaging effect for this variant. Details ▾Hide ▴
Still missing
  • No functional studies available for this variant
BS4 No family segregation data are available to assess lack of segregation with disease. Details ▾Hide ▴
Still missing
  • No family segregation data available
BP1 Insufficient evidence to determine whether TET2-associated germline disease is primarily caused by truncating variants. While TET2 loss-of-function is a supported disease mechanism, the relative contribution of missense versus truncating variants has not been established. Details ▾Hide ▴
Evidence considered
  • TET2 germline disease includes both loss-of-function and missense variants
  • variant spectrum not sufficiently characterized for BP1
Still missing
  • Gene-level variant spectrum data (truncating vs. missense burden) not available
BP2 No phase data (cis or trans) are available for this variant with respect to any other variant in TET2. Details ▾Hide ▴
Still missing
  • No phase data available
BP5 No data are available indicating that this variant is found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
  • No alternate molecular diagnosis data available
PS5 No reputable source has classified this missense variant as pathogenic, and no same-residue pathogenic comparator variants were identified to support PS5 application. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no expert panel classification exists
  • No same-residue pathogenic missense variants identified by PM5 candidate search
Still missing
  • No variant-specific evidence of disease causation available
Sources
clinvar ↗pm5_candidates
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001127208.2:c.5651C>A is a missense variant (p.Thr1884Asn) and does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The generic PVS1 decision tree (PMC6185798) is not applicable to missense substitutions. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution (c.5651C>A
  • p.Thr1884Asn)
  • PVS1 variant assessment classifies this as bucket 'other'
  • apply_generic_pvs1_framework=false
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/ANo pathogenic variant with the same amino acid change (p.Thr1884Asn) has been established in ClinVar or the literature. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no same-amino-acid pathogenic comparator exists
Sources
clinvar ↗
PS2 N/ANo de novo testing data (with confirmed paternity and maternity) are available for this variant. Details ▾Hide ▴
Still missing
  • No family studies or de novo testing data available
PM3 N/APM3 requires detection in trans with a known pathogenic variant. No phase data or trans observations are available. Details ▾Hide ▴

No further detail was recorded.

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

No further detail was recorded.

PM5 N/ANo pathogenic missense variant has been identified at amino acid residue Thr1884 to serve as a PM5 comparator. The automated PM5 candidate search found zero same-residue candidates. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: 0 same-residue candidates
  • recommendation level: not_applicable
Sources
pm5_candidates
BP3 N/ABP3 applies only to in-frame deletions/insertions in a repetitive region. This is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies only to synonymous variants. NM_001127208.2:c.5651C>A is a missense substitution (p.Thr1884Asn). Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
TET2
Transcript
NM_001127208.2
Coding (HGVS c.)
NM_001127208.2:c.5651C>A
Protein (HGVS p.)
NP_001120680.1:p.(Thr1884Asn)
GRCh38
chr4:105276161 C>A
GRCh37
chr4:106197318 C>A
COSMIC
COSV54403709

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 0 / 1,551,598 alleles AF 0 · 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 0 · 0 / 1,551,598 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1551598 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73134 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 +59 bp
0.000
SpliceAI acceptor gainat +37 bp
0.000
SpliceAI donor lossat +298 bp
0.000
SpliceAI donor gainat +150 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.302
BayesDel
-0.273

How the predictions were used

BP4 SupportingMultiple lines of computational evidence predict no damaging effect. BayesDel score is -0.27313 (benign prediction), REVEL score is 0.302 (neutral, below pathogenicity threshold), and SpliceAI predicts no splice impact (max delta = 0.00). Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.27313 (benign prediction)
  • REVEL: 0.302 (neutral
  • below 0.5 pathogenicity threshold)
  • SpliceAI: max delta 0.00 (no splice impact)
Sources
revelbayesdelspliceai ↗
PP3 Multiple in silico tools do not support a deleterious effect. REVEL score is 0.302 (below the typical pathogenicity threshold of 0.5), BayesDel score is -0.27313 (predicting benign), and SpliceAI predicts no splice impact (max delta = 0.00). Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.302 (neutral
  • below 0.5 pathogenicity threshold)
  • BayesDel score: -0.27313 (benign prediction)
  • SpliceAI max delta: 0.00 (no splice impact predicted)
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies only to synonymous variants. NM_001127208.2:c.5651C>A is a missense substitution (p.Thr1884Asn). Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.302. BayesDel score = -0.27313.

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 0 / 1,551,598 recorded alleles 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

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1551598 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73134 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 = 0.00). REVEL score = 0.302. BayesDel score = -0.27313.

Functional

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54403709, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.