About TET2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TET2 c.3765C>G, p.(Tyr1255Ter)
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Strong
PVS1 · strong
Nonsense variant NM_001127208.2:c.3765C>G (p.Tyr1255Ter) in exon 6 of 11, predicted to undergo nonsense-mediated decay, in a gene where loss of function is an established germline disease mechanism supported by multiple publications (heterozygous germline TET2 LoF variants cause an ALPS-like phenotype with lymphoma predisposition, PMID:36066697, PMID:40031954). Under ClinGen SVI PVS1 recommendations (PMC6185798), this qualifies for PVS1 at strong strength.
PM1Moderate
PM1 · moderate
Variant p.Tyr1255Ter is located within the well-characterized TET2 catalytic domain (residues 1129-1936, structurally resolved at 2.02 Å resolution in PMID:24315485). Position 1255 lies in the Cys-rich domain immediately adjacent to the L1 DNA-interacting loop (residues 1256-1273) that is critical for DNA binding and catalytic activity. The truncation at Y1255 removes the entire C-terminal DSBH catalytic domain essential for 5-methylcytosine oxidation. The TET2 catalytic domain is a well-established functional domain whose disruption is associated with myeloid malignancies.
PM2Supporting
PM2 · supporting
Variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=1.29e-06, 2/1,551,546 alleles, 0 homozygotes; grpmax FAF=2.9e-07), well below the 0.1% PM2 threshold for non-VCEP generic ACMG application.
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 strong, PM1 moderate, PM2 supporting; combination = 1 strong + 1 moderate + 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
2 / 1,551,546 alleles
gnomAD v4.1: 2 / 1,551,546 alleles. Recorded AF 1.28904e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.050 maximum delta
Recorded SpliceAI maximum delta score: 0.050. 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 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
5 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV54400069, 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.
29 criteria with recorded statuses: 3 met · 16 not met · 1 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PVS1 (strong): NM_001127208.2:c.3765C>G is a nonsense variant (p.Tyr1255Ter) in exon 6 of 11, predicted to undergo nonsense-mediated decay. TET2 loss of function is an established germline disease mechanism, with heterozygous LoF variants causing an ALPS-like phenotype with lymphoma predisposition.
PM1 (moderate): p.Tyr1255Ter is located within the well-characterized TET2 catalytic domain (residues 1129-1936, crystallographically resolved at 2.02 Å). Position 1255 lies in the Cys-rich domain adjacent to the critical L1 DNA-interacting loop. This truncation removes the C-terminal DSBH catalytic domain essential for 5-methylcytosine oxidation.
PM2 (supporting): The variant is absent from gnomAD v2.1 and present at an extremely low frequency in gnomAD v4.1 (AF=1.29e-06, 2/1,551,546 alleles, no homozygotes), well below the 0.1% threshold.
Overall classification: 1 strong (PVS1) + 1 moderate (PM1) + 1 supporting (PM2) meets the ACMG/AMP threshold for Likely Pathogenic.
No criteria match.
Met · 3
PVS1 StrongNonsense variant NM_001127208.2:c.3765C>G (p.Tyr1255Ter) in exon 6 of 11, predicted to undergo nonsense-mediated decay, in a gene where loss of function is an established germline disease mechanism supported by multiple publications (heterozygous germline TET2 LoF variants cause an ALPS-like phenotype with lymphoma predisposition, PMID:36066697, PMID:40031954). Under ClinGen SVI PVS1 recommendations (PMC6185798), this qualifies for PVS1 at strong strength. Details ▾Hide ▴
Evidence considered
- Nonsense variant p.Tyr1255Ter in exon 6 of 11 exons
- NMD predicted
- TET2 loss of function is an established germline disease mechanism (heterozygous germline LoF variants associated with ALPS-like phenotype and hematologic malignancy)
- PVS1 gene gate: eligible per generic PMC6185798 framework
Sources
PM1 ModerateVariant p.Tyr1255Ter is located within the well-characterized TET2 catalytic domain (residues 1129-1936, structurally resolved at 2.02 Å resolution in PMID:24315485). Position 1255 lies in the Cys-rich domain immediately adjacent to the L1 DNA-interacting loop (residues 1256-1273) that is critical for DNA binding and catalytic activity. The truncation at Y1255 removes the entire C-terminal DSBH catalytic domain essential for 5-methylcytosine oxidation. The TET2 catalytic domain is a well-established functional domain whose disruption is associated with myeloid malignancies. Details ▾Hide ▴
Evidence considered
- PMID:24315485 — crystal structure defines TET2 catalytic domain as residues 1129-1936
- Y1255 is within the Cys-rich domain near L1 DNA-interacting loop (residues 1256-1273)
- PMID:21057493 — confirms TET2 catalytic function in 5mC-to-5hmC conversion and establishes functional importance of the catalytic domain
- Truncation at Y1255 removes the DSBH domain (residues ~1380-1936) containing the Fe(II)-chelating catalytic core
Sources
PM2 SupportingVariant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=1.29e-06, 2/1,551,546 alleles, 0 homozygotes; grpmax FAF=2.9e-07), well below the 0.1% PM2 threshold for non-VCEP generic ACMG application. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- gnomAD v4.1: AF=1.29e-06 (2/1
- 551
- 546 alleles)
- 0 homozygotes
- grpmax FAF=2.9e-07
Sources
Not met · 16 · evaluated, threshold not reached
PS2 No de novo data for this variant is available in the case materials or literature reviewed. De novo confirmation (with maternity and paternity confirmed) is required to apply PS2. Details ▾Hide ▴
Still missing
- No de novo testing data available
PS3 No experimental functional data exists for the specific variant p.Tyr1255Ter or for a systematically characterized residue range that includes position 1255. The functional studies reviewed (PMID:21057493, PMID:24315485) tested selected missense residues within the TET2 catalytic domain but did not include Y1255 or any truncating variant, and the sparse testing pattern does not constitute a systematic range characterization qualifying for PS3. Domain-level knowledge supports PM1 but not variant-level PS3. Details ▾Hide ▴
Evidence considered
- PMID:21057493 — functional assays of TET2 catalytic activity tested specific missense mutants (H1302Y
- D1304A
- H1802R
- H1802Q
- P1287S
- W1211R
- C1834D
- R1817S/M)
- Y1255 not tested
- PMID:24315485 — crystal structure of TET2 catalytic domain (residues 1129-1936)
- Y1255 located in Cys-rich domain near L1 DNA-interacting loop but not functionally characterized
Still missing
- No variant-specific functional assay data available
Sources
PS4 No case-control data or proband counts are available for this variant. The variant is absent from ClinVar and has no documented germline observations beyond gnomAD. Details ▾Hide ▴
Still missing
- No case-control or cohort data available
PM5 No pathogenic missense variant at codon 1255 was identified. The variant is a nonsense change (p.Tyr1255Ter) and the canonical PM5 definition applies to missense variants with a different pathogenic missense at the same codon. PM5 candidate harvest found zero same-residue candidates. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic comparators in ClinVar
Sources
pm5_candidates
PM6 No de novo data (with confirmed maternity and paternity) is available for this variant. Details ▾Hide ▴
Still missing
- No de novo testing data
PP1 No co-segregation data or pedigree information is available for this variant. Details ▾Hide ▴
Still missing
- No segregation or pedigree data
PP5 Variant is absent from ClinVar. No reputable source has classified this variant as pathogenic, so PP5 cannot be applied. Details ▾Hide ▴
BA1 Allele frequency in gnomAD v4.1 is 1.29e-06, far below the 1% BA1 threshold. Variant is absent from gnomAD v2.1 and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF=1.29e-06 (2/1
- 551
- 546) — far below 1%
- Absent from gnomAD v2.1 and gnomAD-Canada v1.0
Sources
BS1 Allele frequency in gnomAD v4.1 is 1.29e-06, far below the 0.3% BS1 threshold for generic ACMG application. Details ▾Hide ▴
BS2 No homozygotes are observed in gnomAD v4.1 (0 homozygotes out of 1,551,546 alleles). BS2 requires observation in a homozygous state in a healthy adult. Details ▾Hide ▴
BS3 No in vitro or in vivo functional studies demonstrating no damaging effect are available for this variant. Details ▾Hide ▴
Still missing
- No benign functional data available
BS4 No segregation data are available. BS4 requires lack of co-segregation with disease in affected family members. Details ▾Hide ▴
Still missing
- No family segregation data
BP2 No observation of this variant in trans with a known pathogenic variant for TET2-related disease. Details ▾Hide ▴
No further detail was recorded.
BP5 No evidence that this variant was observed in a case with an alternate molecular basis for disease. Details ▾Hide ▴
No further detail was recorded.
BP6 Variant is absent from ClinVar. No reputable source has classified this variant as benign, so BP6 cannot be applied. Details ▾Hide ▴
PS5 No prior classification exists for p.Tyr1255Ter or any other pathogenic variant at codon 1255. The variant is absent from ClinVar, and PM5 candidate harvest found no same-residue comparator variants. Details ▾Hide ▴
Evidence considered
- No pathogenic comparators at codon 1255 identified in ClinVar
Sources
pm5_candidates
Not assessed · 1 · no assessment recorded
PP4 No patient phenotype or clinical history data were provided in the case materials. PP4 requires phenotype specificity assessment, which cannot be performed without clinical context. Details ▾Hide ▴
Still missing
- Patient phenotype and clinical history not provided
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AVariant is a nonsense change (p.Tyr1255Ter), not a missense variant; PS1 applies only when a different nucleotide change at the same position results in the same amino acid change as a known pathogenic variant. Details ▾Hide ▴
No further detail was recorded.
PM3 N/APM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant. TET2-related disease is autosomal dominant/heterozygous; no recessive model is established. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AVariant is a nonsense substitution, not a protein-length-altering in-frame deletion/insertion or stop-loss variant. PM4 applies to non-repeat in-frame indels and stop-loss variants. Details ▾Hide ▴
No further detail was recorded.
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This variant is a nonsense change, not a missense variant. Details ▾Hide ▴
No further detail was recorded.
PP3 N/ANonsense variant; in silico tools (REVEL, BayesDel, SpliceAI) are calibrated for missense variants and do not meaningfully assess the impact of a premature termination codon. The deleterious effect of protein truncation is already captured by PVS1. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.05 — no cryptic splice site creation
- BayesDel score 0.023797 — not applicable to nonsense variants
Sources
spliceai ↗bayesdel
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This variant is itself a truncating (nonsense) change, so BP1 does not apply. Details ▾Hide ▴
No further detail was recorded.
BP3 N/AVariant is a substitution, not an in-frame deletion or insertion. BP3 applies to in-frame indels in repetitive regions without a known function. Details ▾Hide ▴
No further detail was recorded.
BP4 N/ANonsense variant; in silico tools (REVEL, BayesDel) are calibrated for missense variants. SpliceAI max delta is 0.05, indicating no cryptic splicing impact. The benign-read of in silico scores is irrelevant for a protein-truncating variant. Details ▾Hide ▴
BP7 N/AVariant is a nonsense change (c.3765C>G, p.Tyr1255Ter), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- TET2
- Transcript
- NM_001127208.2
- Coding (HGVS c.)
- NM_001127208.2:c.3765C>G
- Protein (HGVS p.)
- NP_001120680.1:p.(Tyr1255Ter)
- GRCh38
- chr4:105243740 C>G
- GRCh37
- chr4:106164897 C>G
- COSMIC
- COSV54400069
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
2 / 1,551,546 alleles
AF 1.29e-06 · 0 homozygotes · FAF 2.9e-07
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.3e-06 · 2 / 1,551,546 alleles · 0 hom · FAF 2.9e-07
| European (non-Finnish)2 / 1,146,936 | 1.7e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.28904e-06; MAF= 0.00013%, 2/1551546 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.74378e-06; MAF= 0.00017%, 2/1146936 alleles, homozygotes = 0); grpmax FAF= 2.9e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.024
How the predictions were used
PP3 N/ANonsense variant; in silico tools (REVEL, BayesDel, SpliceAI) are calibrated for missense variants and do not meaningfully assess the impact of a premature termination codon. The deleterious effect of protein truncation is already captured by PVS1. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.05 — no cryptic splice site creation
- BayesDel score 0.023797 — not applicable to nonsense variants
Sources
spliceai ↗bayesdel
BP4 N/ANonsense variant; in silico tools (REVEL, BayesDel) are calibrated for missense variants. SpliceAI max delta is 0.05, indicating no cryptic splicing impact. The benign-read of in silico scores is irrelevant for a protein-truncating variant. Details ▾Hide ▴
BP7 N/AVariant is a nonsense change (c.3765C>G, p.Tyr1255Ter), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). BayesDel score = 0.023797.
2 paper records listed. 2 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Cited in the classification
-
PMID 21057493 ↗Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2.Characterizes TET2 as a 5-methylcytosine dioxygenase that converts 5mC to 5hmC. Functional assays tested specific missense mutations (H1302Y, D1304A, H1802R, H1802Q, P1287S, W1211R, C1834D, R1817S/M) in the TET2 catalytic domain. Confirms that mutations in Fe(II)-chelating and 2OG-binding residues abolish catalytic activity.→ PM1 Does not name this variant
Source detail
HEK293T cells expressing Tet2 mutants H1802R and H1802Q showed greatly diminished 5-hmC staining and no loss of 5-mC staining, consistent with participation of this residue in catalysis.
Location Results section; Figure 1; Supplementary Figures 1-4
Context HEK293T cells, Myc-tagged murine Tet2 overexpression, immunocytochemistry for 5hmC/5mC, dot blot assays
-
PMID 24315485 ↗Crystal structure of TET2-DNA complex: insight into TET-mediated 5mC oxidation.Reports the crystal structure of human TET2 catalytic domain (residues 1129-1936) bound to methylated DNA at 2.02 Å resolution. Defines the Cys-rich and DSBH domains, DNA-interacting loops L1 (residues 1256-1273) and L2 (residues 1288-1312), and Fe(II)/2OG-chelating residues. Residue Y1255 is located at the boundary of the Cys-rich domain immediately before the L1 DNA-binding loop.→ PM1 Does not name this variant
Source detail
Loop L2 (residues 1288–1312) is inserted into the minor groove of DNA, and L1 (residues 1256–1273) supports DNA on the other side.
Location Results: Structure Determination; Overall Structure; Figures 1, 3, 4
Context X-ray crystallography, HEK293T cells for activity assays of mutant constructs, LC-MS/MS for in vitro enzymatic activity
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
2 / 1,551,546 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.050
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.3765C%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/4-106164897-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr4-105243740-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/4-105243740-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001127208.2%3Ac.3…
- OncoKB ↗www.oncokb.org/gene/TET2/Y1255*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=194824323
- 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= 1.28904e-06; MAF= 0.00013%, 2/1551546 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.74378e-06; MAF= 0.00017%, 2/1146936 alleles, homozygotes = 0); grpmax FAF= 2.9e-07.
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 = 0.05). BayesDel score = 0.023797.
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; COSV54400069, n = 5 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.