About TET2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TET2 c.1452T>A, p.(Cys484Ter)
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.
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
This variant is a nonsense change, NM_001127208.2:c.1452T>A, predicted to cause p.(Cys484Ter) / p.(C484*) in exon 3, with truncation very early in the coding sequence (codon 484 of 2003). Available gene-level evidence supports germline TET2 loss of function as a disease mechanism, and the generic ClinGen SVI PVS1 framework indicates that this type of variant is eligible for PVS1; the early position is consistent with a null effect through truncation or nonsense-mediated decay.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the non-VCEP rarity threshold of 0.1% and supports rarity in population databases.
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 supporting; combination = 1 very strong + 1 supporting, 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.
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.
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
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 · 4 not met · 14 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.1452T>A (p.(Cys484Ter)) variant has not been reported in ClinVar.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the 0.1% rarity threshold used for non-VCEP PM2 assessment.
This nonsense variant introduces a premature stop codon early in the coding sequence, and available gene-level evidence supports germline TET2 loss of function as a disease mechanism, supporting PVS1 application under the generic ClinGen SVI framework.
SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, no REVEL score was available, and the available BayesDel score was 0.122979; these computational data were reviewed but do not outweigh the independent truncating effect of the variant.
No criteria match.
Met · 2
PVS1 Very strongThis variant is a nonsense change, NM_001127208.2:c.1452T>A, predicted to cause p.(Cys484Ter) / p.(C484*) in exon 3, with truncation very early in the coding sequence (codon 484 of 2003). Available gene-level evidence supports germline TET2 loss of function as a disease mechanism, and the generic ClinGen SVI PVS1 framework indicates that this type of variant is eligible for PVS1; the early position is consistent with a null effect through truncation or nonsense-mediated decay. Details ▾Hide ▴
Rule
Generic ACMG/AMP PVS1 using ClinGen SVI PVS1 recommendations (PMC6185798) after gene-level loss-of-function eligibility was established.
Evidence considered
- Nonsense variant p.(Cys484Ter) / p.(C484*)
- Variant lies in exon 3
- Predicted stop at codon 484 of 2003
- Generic PVS1 scaffold suggested default strength PVS1
- Gene-level PVS1 gate marked eligible because germline TET2 loss of function is supported
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the non-VCEP rarity threshold of 0.1% and supports rarity in population databases. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM2 at supporting strength for absence from population databases in this non-VCEP review context.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- Observed population frequency effectively 0
- below 0.1% threshold
Sources
Not met · 4 · evaluated, threshold not reached
PM1 Available evidence does not place this variant in a confirmed mutational hotspot or a narrowly defined critical region without benign variation. Cancer Hotspots did not identify a significant hotspot at this residue, and the retrieved TET2 structural literature concerns the catalytic C-terminal region rather than this early truncating position. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM1.
Evidence considered
- Cancer Hotspots review did not identify a significant hotspot at C484
- Structural paper localizes critical catalytic features to the C-terminal catalytic region
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and is therefore well below the benign stand-alone threshold of 1.0%. Details ▾Hide ▴
Rule
Generic ACMG/AMP BA1.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- Observed population frequency effectively 0
- below 1.0% threshold
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not exceed the benign strong threshold of 0.3%. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS1.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- Observed population frequency effectively 0
- below 0.3% threshold
Sources
BP4 Available computational evidence does not support a benign interpretation. SpliceAI predicts no significant splice impact with a max delta score of 0.00, but this does not offset the independent protein-truncating effect of the nonsense variant, and the available BayesDel score of 0.122979 is not benign-supporting evidence for this context. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP4.
Evidence considered
- SpliceAI max delta score 0.00
- BayesDel score 0.122979
- REVEL not found
Sources
spliceai ↗bayesdel
Not assessed · 14 · no assessment recorded
PS1 No evidence was identified that a different nucleotide change causing the same amino acid effect has already been established as pathogenic or likely pathogenic for this gene-disease context. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS1.
Evidence considered
- ClinVar search returned no exact record
Still missing
- No same-amino-acid established pathogenic comparator was identified.
Sources
PS2 No confirmed de novo observation with verified maternity and paternity was identified for this variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS2.
Evidence considered
- ClinVar search returned no exact record
Still missing
- No trio-based germline case report or submitter note confirming de novo status was identified.
Sources
PS3 Published TET2 functional and structural literature was identified, but the available evidence does not show a well-established functional assay result for this exact variant that can be applied directly as strong pathogenic evidence. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS3 requires well-established functional studies for the specific variant.
Evidence considered
- OncoKB linked functional literature for TET2
- PMID:21057493 describes impaired catalytic activity for TET2 mutations in myeloid malignancies at the gene level
- PMID:24315485 describes TET2 structural/catalytic domains at the gene level
Still missing
- No exact-variant well-established functional assay result was identified in the retrieved evidence.
Sources
PS4 No affected-case enrichment, case-control comparison, or established excess of this exact variant in individuals with a relevant germline phenotype was identified. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS4.
Evidence considered
- ClinVar search returned no exact record
Still missing
- No germline case series or case-control data for this exact variant were identified.
Sources
PM6 No assumed de novo observation without parental confirmation was identified for this variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM6.
Evidence considered
- ClinVar search returned no exact record
Still missing
- No germline case report describing an assumed de novo occurrence was identified.
Sources
PP1 No segregation data were identified for this variant in affected family members. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP1.
Evidence considered
- ClinVar search returned no exact record
Still missing
- No pedigree-based segregation report was identified.
Sources
PP4 No phenotype description specific enough to establish a highly specific TET2-related clinical presentation for this individual was available for PP4 assessment. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP4.
Still missing
- Case-level phenotype specificity was not provided for PP4 evaluation.
PP5 No reputable pathogenic classification source with sufficient supporting details was identified for this exact variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP5.
Evidence considered
- ClinVar search returned no exact record
Still missing
- No exact-variant pathogenic assertion from a qualifying external source was identified.
Sources
BS2 No data were identified showing this variant in well-characterized healthy adult individuals for whom the relevant phenotype would be expected to be penetrant. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS2.
Still missing
- No healthy adult carrier data were identified.
BS3 Published TET2 functional literature was identified, but the available evidence does not show a well-established normal functional result for this exact variant that could support a benign interpretation. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS3.
Evidence considered
- OncoKB linked functional literature for TET2
- Retrieved papers are gene-level functional/structural studies rather than normal-function studies for this exact variant
Still missing
- No exact-variant well-established functional assay showing normal function was identified.
Sources
BS4 No non-segregation data were identified for this variant in a family setting. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS4.
Evidence considered
- ClinVar search returned no exact record
Still missing
- No family study showing lack of segregation with disease was identified.
Sources
BP2 No phase information or co-occurrence data with another pathogenic variant were identified. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP2.
Still missing
- No cis/trans co-occurrence data were identified.
BP5 No alternative molecular diagnosis or other clear cause of disease was identified that would make this variant an incidental finding. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP5.
Still missing
- No case-level alternative diagnosis information was available.
BP6 No reputable benign classification source was identified for this exact variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP6.
Evidence considered
- ClinVar search returned no exact record
Still missing
- No exact-variant benign assertion from a qualifying external source was identified.
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/AThis criterion is intended for recessive disorders with pathogenic variants observed in trans, and that evidence context was not applicable here. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM3.
PM4 N/AThis criterion applies to protein length changes such as in-frame insertions/deletions or stop-loss variants and is not applicable to this nonsense variant already addressed under PVS1. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM4.
Evidence considered
- Variant bucket identified as nonsense
Sources
pvs1_variant_assessment
PM5 N/AThis criterion applies to novel missense changes at an amino acid residue where a different pathogenic missense change is established, and this variant is a nonsense change. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM5.
Evidence considered
- Variant bucket identified as nonsense
Sources
pvs1_variant_assessment
PP2 N/AThis criterion applies to missense variants in genes with low rates of benign missense variation and a disease mechanism enriched for missense change, which is not applicable to this nonsense variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP2.
Evidence considered
- Variant bucket identified as nonsense
Sources
pvs1_variant_assessment
PP3 N/AComputational splice prediction does not indicate an added splice effect, with SpliceAI max delta score 0.00, and no REVEL score was available. A BayesDel score of 0.122979 was present, but missense-style computational prediction is not the relevant basis for pathogenic scoring in this early nonsense variant, which is already addressed by PVS1. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP3; computational evidence was reviewed but not applied independently for this nonsense variant.
Evidence considered
- SpliceAI max delta score 0.00
- REVEL not found
- BayesDel score 0.122979
- Variant bucket identified as nonsense
Sources
BP1 N/AThis criterion applies to missense variants, whereas this variant is a nonsense change. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP1.
Evidence considered
- Variant bucket identified as nonsense
Sources
pvs1_variant_assessment
BP3 N/AThis criterion applies to in-frame insertions or deletions in repetitive regions without known function and is not applicable to this nonsense variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP3.
Evidence considered
- Variant bucket identified as nonsense
Sources
pvs1_variant_assessment
BP7 N/AThis criterion applies to synonymous or certain intronic variants with no predicted splice impact and is not applicable to this nonsense variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP7.
Evidence considered
- Variant bucket identified as nonsense
- SpliceAI max delta score 0.00
Sources
pvs1_variant_assessmentspliceai ↗
Identifiers
- Gene
- TET2
- Transcript
- NM_001127208.2
- Coding (HGVS c.)
- NM_001127208.2:c.1452T>A
- Protein (HGVS p.)
- NP_001120680.1:p.(Cys484Ter)
- GRCh38
- chr4:105235394 T>A
- GRCh37
- chr4:106156551 T>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
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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
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
BP4 Available computational evidence does not support a benign interpretation. SpliceAI predicts no significant splice impact with a max delta score of 0.00, but this does not offset the independent protein-truncating effect of the nonsense variant, and the available BayesDel score of 0.122979 is not benign-supporting evidence for this context. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP4.
Evidence considered
- SpliceAI max delta score 0.00
- BayesDel score 0.122979
- REVEL not found
Sources
spliceai ↗bayesdel
PP3 N/AComputational splice prediction does not indicate an added splice effect, with SpliceAI max delta score 0.00, and no REVEL score was available. A BayesDel score of 0.122979 was present, but missense-style computational prediction is not the relevant basis for pathogenic scoring in this early nonsense variant, which is already addressed by PVS1. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP3; computational evidence was reviewed but not applied independently for this nonsense variant.
Evidence considered
- SpliceAI max delta score 0.00
- REVEL not found
- BayesDel score 0.122979
- Variant bucket identified as nonsense
Sources
BP7 N/AThis criterion applies to synonymous or certain intronic variants with no predicted splice impact and is not applicable to this nonsense variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP7.
Evidence considered
- Variant bucket identified as nonsense
- SpliceAI max delta score 0.00
Sources
pvs1_variant_assessmentspliceai ↗
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.122979.
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_001127208.2%3Ac.1452T%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/4-106156551-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr4-105235394-T-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001127208.2%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/TET2/C484*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=163701356
- 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
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). BayesDel score = 0.122979.
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 previously been reported in somatic cancers (COSMIC; COSV54411152, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.