About TET2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TET2 c.3784C>T, p.(Arg1262Trp)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
This variant is rare in population databases. In gnomAD v2.1 it was seen at 0.00319% overall (1/31,394 alleles) with a highest subpopulation frequency of 0.00648% (1/15,424 alleles), and in gnomAD v4.1 it was seen at 0.00045% overall (7/1,551,328 alleles) with a highest subpopulation frequency of 0.00244% (1/40,926 alleles); these values are below the 0.1% PM2 threshold.
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: PM2 moderate; combination = 1 moderate, 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
7 / 1,551,328 alleles
gnomAD v4.1: 7 / 1,551,328 alleles. Recorded AF 4.51226e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18532e-05; MAF= 0.00319%, 1/31394 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.4834e-05; MAF= 0.00648%, 1/15424 alleles, homozygotes = 0).
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. 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 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
5 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV54399852, n = 5 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 14 not met · 5 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The TET2 c.3784C>T (p.Arg1262Trp; p.R1262W) variant has not been reported in ClinVar.
This variant is present at low frequency in gnomAD v2.1 and v4.1, with the highest observed frequency 0.00648% (1/15,424 alleles) in European non-Finnish individuals in gnomAD v2.1, which is below the 0.1% PM2 threshold and below the BS1 (>0.3%) and BA1 (>1%) thresholds.
No variant-specific functional study establishing either a damaging effect or normal function was identified; the available published TET2 structural study provides protein-domain context but does not assay p.Arg1262Trp directly.
Computational evidence is mixed overall: SpliceAI predicts no significant splice impact (max delta score 0.02), while REVEL is 0.536 and BayesDel is 0.118577, which does not provide concordant support for either PP3 or BP4.
No criteria match.
Met · 1
PM2 ModerateThis variant is rare in population databases. In gnomAD v2.1 it was seen at 0.00319% overall (1/31,394 alleles) with a highest subpopulation frequency of 0.00648% (1/15,424 alleles), and in gnomAD v4.1 it was seen at 0.00045% overall (7/1,551,328 alleles) with a highest subpopulation frequency of 0.00244% (1/40,926 alleles); these values are below the 0.1% PM2 threshold. Details ▾Hide ▴
Rule
PM2 applied using default rare-frequency threshold <0.1%.
Evidence considered
- gnomAD v2.1 overall AF 3.18532e-05
- highest subpopulation AF 6.4834e-05
- gnomAD v4.1 overall AF 4.51226e-06
- highest subpopulation AF 2.44343e-05
Sources
Not met · 14 · evaluated, threshold not reached
PS1 No pathogenic or likely pathogenic variant producing the same amino acid change was identified. ClinVar did not contain this variant, and no same-amino-acid comparator supporting PS1 was retrieved. Details ▾Hide ▴
Evidence considered
- ClinVar absent
- No comparator variants retrieved for same residue/amino-acid logic
Still missing
- No same-amino-acid pathogenic comparator was identified.
Sources
clinvar ↗pm5_candidates
PS2 No confirmed de novo occurrence with established maternity and paternity was identified for this variant. Details ▾Hide ▴
Evidence considered
- No ClinVar submissions or literature-backed de novo evidence retrieved
Still missing
- No trio-based de novo report was identified.
Sources
PS3 No well-established functional study showing a damaging effect of p.Arg1262Trp was identified. The retrieved TET2 publication provides structural context for the protein but does not test this variant directly. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence
- Published TET2 structural study is not an assay of p.Arg1262Trp
Still missing
- No variant-specific functional assay was identified.
Sources
PS4 No case-control enrichment data or other evidence showing this variant is significantly more common in affected individuals than in controls was identified. Details ▾Hide ▴
Evidence considered
- ClinVar absent
- Low-frequency population observations in gnomAD
Still missing
- No affected-versus-control enrichment study was identified.
Sources
PM1 Available evidence does not establish that Arg1262 lies in a mutational hotspot or a well-defined critical region without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this residue, and structural domain context alone is not sufficient for PM1. Details ▾Hide ▴
Evidence considered
- No hotspot row found for TET2 R1262
- TET2 structural publication provides domain background only
Still missing
- No residue-level pathogenic clustering evidence was identified.
Sources
PM6 No presumed de novo occurrence of this variant was identified. Details ▾Hide ▴
Evidence considered
- No ClinVar submission or retrieved report documenting presumed de novo status
Still missing
- No presumed de novo report was identified.
Sources
PP1 No segregation data were identified showing that this variant cosegregates with disease in a family. Details ▾Hide ▴
Evidence considered
- No segregation evidence retrieved
Still missing
- No family segregation report was identified.
Sources
PP3 Computational evidence is mixed and does not provide concordant support for a deleterious effect. SpliceAI predicts no significant splice impact with a max delta score of 0.02, while REVEL is 0.536 and BayesDel is 0.118577, which is not sufficient as a consistent multi-tool pathogenic signal. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.02
- REVEL 0.536
- BayesDel 0.118577
Sources
BA1 Population frequency does not meet the stand-alone benign threshold. The highest observed frequency was 0.00648% in gnomAD v2.1, which is far below the 1% BA1 threshold. Details ▾Hide ▴
Rule
BA1 requires frequency >1%.
Evidence considered
- Highest observed subpopulation AF 0.00648% in gnomAD v2.1
Sources
BS1 Population frequency does not exceed the benign strong threshold. The highest observed frequency was 0.00648% in gnomAD v2.1, which is below the 0.3% BS1 threshold. Details ▾Hide ▴
Rule
BS1 requires frequency >0.3%.
Evidence considered
- Highest observed subpopulation AF 0.00648% in gnomAD v2.1
Sources
BS2 The available population data show only rare allele observations and no homozygotes, which does not support observation in healthy adults at a level expected for BS2. Details ▾Hide ▴
Evidence considered
- Rare gnomAD observations with zero homozygotes
Still missing
- No evidence of multiple unaffected adult carriers beyond rare database observations.
Sources
BS3 No well-established functional study showing normal or near-normal function of p.Arg1262Trp was identified. Details ▾Hide ▴
Evidence considered
- No variant-specific reviewed functional evidence retrieved
- Available publication is structural background rather than a normal-function assay
Still missing
- No variant-specific normal-function assay was identified.
Sources
BS4 No data were identified showing lack of segregation of this variant with disease. Details ▾Hide ▴
Evidence considered
- No family-based non-segregation evidence retrieved
Still missing
- No informative non-segregation data were identified.
Sources
BP4 Computational evidence does not provide concordant benign support. SpliceAI predicts no significant splice impact with a max delta score of 0.02, but REVEL is 0.536 and BayesDel is 0.118577, so the overall in silico profile is not consistently benign. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.02
- REVEL 0.536
- BayesDel 0.118577
Sources
Not assessed · 5 · no assessment recorded
PP2 Available evidence does not establish that TET2 is a gene in which missense variation is a common disease mechanism and benign missense variation is unusually low, so PP2 was not assessed. Details ▾Hide ▴
Still missing
- No gene-level missense mechanism calibration was identified.
PP4 No phenotype information was provided that would allow assessment of whether the clinical presentation is highly specific for a TET2-related disorder. Details ▾Hide ▴
Still missing
- Phenotypic specificity data were not available.
BP1 Although germline loss of function is supported as a disease mechanism in TET2, the available evidence does not establish that missense variation is an uncommon pathogenic mechanism in this gene, so BP1 was not assessed. Details ▾Hide ▴
Evidence considered
- Loss of function is a supported mechanism at the gene level
Still missing
- No gene-level calibration showing missense variants are rarely pathogenic.
Sources
pvs1_gene_context
BP2 No phase information or co-occurrence data were identified to assess BP2. Details ▾Hide ▴
Still missing
- No cis/trans co-occurrence data were identified.
BP5 No phenotype data or alternate molecular diagnosis information were available to assess whether another cause fully explains the clinical presentation. Details ▾Hide ▴
Still missing
- No alternate molecular diagnosis data were provided.
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, p.Arg1262Trp (p.R1262W), and available splice prediction does not support a loss-of-function splicing effect. Generic PVS1 was reviewed because germline loss of function is an established disease mechanism for TET2, but this specific variant does not fall into the nonsense, frameshift, or canonical splice categories used for default PVS1 application. Details ▾Hide ▴
Rule
Generic PVS1 fallback applies only to eligible null-variant classes when loss of function is an established disease mechanism.
Evidence considered
- TET2 is eligible for generic PVS1 consideration at the gene level
- Variant-level PVS1 assessment classified this change outside the default null-variant buckets
- SpliceAI max delta score 0.02
Sources
PM3 N/ANo evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disease context, so PM3 is not applicable from the available data. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AThis variant is a missense substitution and does not cause a protein length change from an in-frame insertion, deletion, or stop-loss event. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.Arg1262Trp
PM5 N/APM5 was not applied because classic same-residue PM5 semantics could not be confirmed safely for this gene/framework, and no qualifying same-residue pathogenic comparator was retrieved. Details ▾Hide ▴
Evidence considered
- PM5 candidate file marked the variant not eligible for automatic classic PM5 search
Still missing
- No qualifying same-residue pathogenic comparator was identified.
Sources
pm5_candidates
PP5 N/ANo pathogenic assertion from a reputable external source without available primary evidence was identified for this variant. Details ▾Hide ▴
BP3 N/AThis is not an in-frame insertion or deletion in a repetitive region without known function, so BP3 is not applicable. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ANo benign assertion from a reputable external source without available primary evidence was identified for this variant. Details ▾Hide ▴
BP7 N/AThis variant is missense rather than synonymous or deep intronic, so BP7 is not applicable. Details ▾Hide ▴
Identifiers
- Gene
- TET2
- Transcript
- NM_001127208.2
- Coding (HGVS c.)
- NM_001127208.2:c.3784C>T
- Protein (HGVS p.)
- NP_001120680.1:p.(Arg1262Trp)
- GRCh38
- chr4:105243759 C>T
- GRCh37
- chr4:106164916 C>T
- COSMIC
- COSV54399852
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
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
7 / 1,551,328 alleles
AF 4.51e-06 · 0 homozygotes · FAF 1.28e-06
gnomAD v2.1
1 / 31,394 alleles
AF 3.19e-05 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 4.5e-06 · 7 / 1,551,328 alleles · 0 hom · FAF 1.3e-06
| East Asian1 / 40,926 | 2.4e-05 |
| African/African American1 / 73,004 | 1.4e-05 |
| European (non-Finnish)5 / 1,146,858 | 4.4e-06 |
0 alternate alleles recorded in 7 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 3.2e-05 · 1 / 31,394 alleles · 0 hom
| European (non-Finnish)1 / 15,424 | 6.5e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.51226e-06; MAF= 0.00045%, 7/1551328 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.44343e-05; MAF= 0.00244%, 1/40926 alleles, homozygotes = 0); grpmax FAF= 1.28e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18532e-05; MAF= 0.00319%, 1/31394 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.4834e-05; MAF= 0.00648%, 1/15424 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.536
- BayesDel
- 0.119
How the predictions were used
PP3 Computational evidence is mixed and does not provide concordant support for a deleterious effect. SpliceAI predicts no significant splice impact with a max delta score of 0.02, while REVEL is 0.536 and BayesDel is 0.118577, which is not sufficient as a consistent multi-tool pathogenic signal. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.02
- REVEL 0.536
- BayesDel 0.118577
Sources
BP4 Computational evidence does not provide concordant benign support. SpliceAI predicts no significant splice impact with a max delta score of 0.02, but REVEL is 0.536 and BayesDel is 0.118577, so the overall in silico profile is not consistently benign. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.02
- REVEL 0.536
- BayesDel 0.118577
Sources
BP7 N/AThis variant is missense rather than synonymous or deep intronic, so BP7 is not applicable. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.536. BayesDel score = 0.118577.
1 paper record 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
-
PMID 24315485 ↗Crystal structure of TET2-DNA complex: insight into TET-mediated 5mC oxidation.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
7 / 1,551,328 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_001127208.2%3Ac.3784C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/4-106164916-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr4-105243759-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001127208.2%3Ac.3…
- OncoKB ↗www.oncokb.org/gene/TET2/R1262W
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=163695434
- Cancer hotspots ↗www.cancerhotspots.org/
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= 4.51226e-06; MAF= 0.00045%, 7/1551328 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.44343e-05; MAF= 0.00244%, 1/40926 alleles, homozygotes = 0); grpmax FAF= 1.28e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18532e-05; MAF= 0.00319%, 1/31394 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.4834e-05; MAF= 0.00648%, 1/15424 alleles, homozygotes = 0).
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.536. BayesDel score = 0.118577.
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; COSV54399852, n = 5 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.