0%
TET2c.4164_4167delLikely pathogenic
Print report
Variant interpretation report

TET2 c.4164_4167del, p.(Met1388IlefsTer59)

NM_001127208.2:c.4164_4167del NP_001120680.1:p.(Met1388IlefsTer59) 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.

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 frameshift deletion predicted to cause p.(Met1388IlefsTer59) and truncate the protein well before the normal C-terminus. Germline loss of function is supported as a disease-relevant mechanism for TET2, and the generic ClinGen SVI PVS1 framework supports applying PVS1 for this type of truncating variant.

PM2Moderate
PM2 · moderate

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the non-VCEP PM2 threshold of 0.1% population frequency and supports rarity in reference populations.

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.

No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied
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
Not assessed

No COSMIC evidence statement is recorded in this case.

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 · 2 not met · 15 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The TET2 c.4164_4167del (p.Met1388IlefsTer59; p.M1388Ifs*59) variant has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing it below the 0.1% rarity threshold used for PM2 in non-VCEP review.

Published TET2 studies identified through curated review show that leukemia-associated TET2 alterations impair 5-hydroxymethylcytosine generation, and structural work supports the functional importance of the C-terminal catalytic region, which is consistent with loss of function as a disease-relevant mechanism for truncating variants.

SpliceAI predicts no significant additional splice effect for this deletion, with a maximum delta score of 0.00; REVEL and BayesDel are not available for this variant type.

Met · 2

PVS1 Very strongThis variant is a frameshift deletion predicted to cause p.(Met1388IlefsTer59) and truncate the protein well before the normal C-terminus. Germline loss of function is supported as a disease-relevant mechanism for TET2, and the generic ClinGen SVI PVS1 framework supports applying PVS1 for this type of truncating variant. Details ▾Hide ▴
Evidence considered
  • Frameshift consequence p.(Met1388IlefsTer59)
  • Generic PVS1 scaffold recommends default PVS1 for frameshift variants once LoF mechanism is established
  • TET2 germline loss-of-function mechanism supported in gene context review
Still missing
  • Transcript-specific NMD and exon relevance should be confirmed during final review.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM2 ModerateThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the non-VCEP PM2 threshold of 0.1% population frequency and supports rarity in reference populations. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 2 · evaluated, threshold not reached

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is below the 1% BA1 threshold and BA1 is not met. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is below the 0.3% BS1 threshold and BS1 is not met. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 15 · no assessment recorded

PS2 No confirmed de novo data were identified for this variant, so PS2 cannot be assessed. Details ▾Hide ▴
Still missing
  • Confirmed maternity and paternity
  • Parental testing results
  • Evidence that the variant is constitutional rather than blood-limited
PS3 Published TET2 functional studies were identified, but the retrieved evidence does not show a direct functional assay of this exact deletion. Available evidence therefore does not support applying PS3 at this stage. Details ▾Hide ▴
Evidence considered
  • OncoKB links this variant to curated TET2 functional literature
  • Retrieved papers are gene-level or domain-level rather than exact-variant functional assays
Still missing
  • Direct functional testing of NM_001127208.2:c.4164_4167delGCAG or p.(Met1388IlefsTer59)
Sources
oncokb ↗PMID:21057493 ↗PMID:24315485 ↗
PS4 No exact-variant case enrichment or case-control data were identified for this variant, so PS4 cannot be applied. Details ▾Hide ▴
Evidence considered
  • No ClinVar submission identified for this exact variant
Still missing
  • Exact-variant counts in affected individuals
  • Control comparison data
  • Clarification of germline versus somatic observations if cases are found
Sources
clinvar ↗
PM1 Available evidence does not establish that this variant lies in a confirmed mutational hotspot or a sufficiently defined critical region without benign variation, so PM1 is not assessed. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots review did not identify a significant hotspot at this residue and was flagged for human review
  • Structural literature supports importance of the TET2 catalytic region but does not by itself establish PM1 for this exact site
Still missing
  • Confirmed residue- or region-specific hotspot/domain evidence suitable for PM1
Sources
hotspots ↗PMID:24315485 ↗
PM3 No data were identified showing this variant in trans with another pathogenic variant, so PM3 cannot be assessed. Details ▾Hide ▴
Still missing
  • Phase information
  • Second-variant data in an affected individual if relevant
PM6 No assumed de novo report was identified for this variant, so PM6 cannot be assessed. Details ▾Hide ▴
Still missing
  • Parental testing details
  • Evidence that the variant is constitutional rather than blood-limited
PP1 No segregation data were identified for this variant, so PP1 cannot be assessed. Details ▾Hide ▴
Still missing
  • Pedigree data
  • Affected and unaffected relative testing results
  • Tissue source for testing in relatives
PP4 No phenotype information specific enough for PP4 was identified, so this criterion cannot be assessed. Details ▾Hide ▴
Still missing
  • Detailed clinical phenotype
  • Assessment of phenotype specificity for a TET2-related germline condition
PP5 No qualifying reputable-source pathogenic classification was identified for this exact variant, so PP5 is not assessed. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
Still missing
  • Independent reputable-source pathogenic assertion for this exact variant
Sources
clinvar ↗
BS2 No evidence was identified showing this variant in healthy adult individuals in a manner suitable for BS2, so the criterion is not assessed. Details ▾Hide ▴
Still missing
  • Well-documented observations in healthy adults with appropriate tissue source and phenotype context
BS3 Available evidence does not show well-established functional studies demonstrating a normal effect for this exact deletion, so BS3 cannot be applied. Details ▾Hide ▴
Evidence considered
  • Retrieved functional literature is not a normal-function assay for this exact variant
Still missing
  • Direct exact-variant functional evidence showing retained normal function
Sources
oncokb ↗PMID:21057493 ↗PMID:24315485 ↗
BS4 No non-segregation data were identified for this variant, so BS4 cannot be assessed. Details ▾Hide ▴
Still missing
  • Family data showing lack of segregation
  • Penetrance and tissue-source context for tested relatives
BP2 No data were identified showing this variant in cis with a pathogenic variant or in trans in a manner supporting BP2, so the criterion is not assessed. Details ▾Hide ▴
Still missing
  • Phase information with another variant
  • Appropriate inheritance and phenotype context
BP5 No alternate molecular explanation for a specific phenotype was identified, so BP5 cannot be assessed. Details ▾Hide ▴
Still missing
  • Phenotype-specific alternative cause data
BP6 No qualifying reputable-source benign classification was identified for this exact variant, so BP6 is not assessed. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
Still missing
  • Independent reputable-source benign assertion for this exact variant
Sources
clinvar ↗
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to a different nucleotide change producing the same amino acid substitution. This variant is a frameshift deletion, so PS1 is not applicable. Details ▾Hide ▴
Evidence considered
  • Variant consequence is frameshift
  • not an alternate missense change encoding the same amino acid substitution
PM4 N/APM4 is generally used for protein length changes from in-frame indels or stop-loss variants. This variant is a frameshift truncating variant already captured by PVS1, so PM4 is not applied separately. Details ▾Hide ▴
Evidence considered
  • Variant is a frameshift truncating event
Sources
pvs1_variant_assessment
PM5 N/APM5 applies to a novel missense change at an amino acid residue where a different pathogenic missense change is established. This variant is a frameshift deletion, so PM5 is not applicable. Details ▾Hide ▴
Evidence considered
  • Variant consequence is frameshift
  • not missense
PP2 N/APP2 is a missense-based criterion and is not applicable to this frameshift deletion. Details ▾Hide ▴
Evidence considered
  • Variant consequence is frameshift
  • not missense
PP3 N/APP3 is not applied here because this variant is a frameshift deletion rather than a missense or splice-consensus change requiring computational pathogenicity support. SpliceAI showed no significant additional splice effect (max delta score 0.00), and REVEL and BayesDel are not available for this deletion. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00
  • REVEL not available for this deletion
  • BayesDel not available for this deletion
Sources
spliceai ↗
BP1 N/ABP1 is a missense-based criterion and is not applicable to this frameshift deletion. Details ▾Hide ▴
Evidence considered
  • Variant consequence is frameshift
  • not missense
BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions without known function. This variant is a frameshift deletion, so BP3 is not applicable. Details ▾Hide ▴
Evidence considered
  • Variant consequence is frameshift
  • not in-frame
BP4 N/ABP4 is not applied here because this variant is a frameshift deletion rather than a variant type for which benign computational protein prediction is informative. SpliceAI predicts no significant additional splice effect (max delta score 0.00), but that does not outweigh the truncating consequence. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous or certain intronic variants with no predicted splice impact. This variant is a coding frameshift deletion, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • Variant is a coding frameshift deletion
  • SpliceAI max delta score 0.00
Sources
spliceai ↗

Identifiers

Gene
TET2
Transcript
NM_001127208.2
Coding (HGVS c.)
NM_001127208.2:c.4164_4167del
Protein (HGVS p.)
NP_001120680.1:p.(Met1388IlefsTer59)
GRCh38
chr4:105269728 TGCAG>T
GRCh37
chr4:106190885 TGCAG>T

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 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/APP3 is not applied here because this variant is a frameshift deletion rather than a missense or splice-consensus change requiring computational pathogenicity support. SpliceAI showed no significant additional splice effect (max delta score 0.00), and REVEL and BayesDel are not available for this deletion. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00
  • REVEL not available for this deletion
  • BayesDel not available for this deletion
Sources
spliceai ↗
BP4 N/ABP4 is not applied here because this variant is a frameshift deletion rather than a variant type for which benign computational protein prediction is informative. SpliceAI predicts no significant additional splice effect (max delta score 0.00), but that does not outweigh the truncating consequence. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous or certain intronic variants with no predicted splice impact. This variant is a coding frameshift deletion, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • Variant is a coding frameshift deletion
  • SpliceAI max delta score 0.00
Sources
spliceai ↗

Statement

In silico

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

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 Captured SpliceAI source record 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.

ClinVar

This variant is absent from ClinVar.

In silico

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

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.