About TET2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TET2 c.4354C>T, p.(Arg1452Ter)
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
This variant is a nonsense change (c.4354C>T, p.Arg1452Ter) predicted to result in premature termination and nonsense-mediated decay (NMD) in a gene where loss of function is an established germline disease mechanism. The variant is located in exon 10 of 11 and is not predicted to escape NMD. TET2 germline loss-of-function mutations are associated with an ALPS-like immune dysregulation syndrome with predisposition to hematologic malignancy (PMID:36066697, PMID:40031954). Under PMC6185798, nonsense variants in genes with established LoF disease mechanism qualify for PVS1 at full strength when not in the terminal exon.
PM1Moderate
PM1 · moderate
The variant truncates the TET2 protein at position 1452, which lies within the catalytic domain (residues 1129-1936 as defined by PMID:24315485). The truncation removes the DSBH core and C-terminal catalytic machinery including Fe(II)-chelating residues (H1881), 2OG-interacting residues (R1896), and DNA-interacting loops. The catalytic domain is a well-characterized functional domain critical for TET2's 5-methylcytosine dioxygenase activity. Truncating variants that remove this domain abrogate TET2 enzymatic function.
PM2Supporting
PM2 · supporting
This variant is present in gnomAD at extremely low allele frequency: v2.1 AF=1.28e-5 (0.00128%, 2/156592 alleles), v4.1 AF=9.67e-6 (0.00097%, 15/1551500 alleles), well below the 0.1% threshold for PM2. It is absent from gnomAD-Canada. No homozygotes have been observed in any population database.
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
15 / 1,551,500 alleles
gnomAD v4.1: 15 / 1,551,500 alleles. Recorded AF 9.66806e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.2772e-05; MAF= 0.00128%, 2/156592 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.10373e-05; MAF= 0.00810%, 2/24680 alleles, homozygotes = 0); grpmax FAF= 1.341e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001086484137331595, 2/18408 alleles, homozygotes = 0).
SpliceAI score
0.160 maximum delta
Recorded SpliceAI maximum delta score: 0.160. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
1 Uncertain significance · 1 Pathogenic. ClinVar API review status: criteria provided, conflicting classifications.
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
27 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV54398405, n = 27 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.
26 criteria with recorded statuses: 3 met · 14 not met · 4 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001127208.2:c.4354C>T (p.Arg1452Ter) is a nonsense variant in exon 10 of 11 of TET2, predicted to result in nonsense-mediated decay and loss of protein function.
TET2 germline loss-of-function mutations are associated with an ALPS-like immune dysregulation syndrome and predisposition to hematologic malignancy, with heterozygous LoF variants reported to cause disease in multiple families.
This variant has been observed in gnomAD at extremely low frequency (v2.1: 2/156592 alleles, AF=0.00128%; v4.1: 15/1551500 alleles, AF=0.00097%) with no homozygotes, and is absent from gnomAD-Canada.
The variant truncates the protein at residue 1452 within the catalytic domain (residues 1129-1936), removing critical functional regions including the DSBH core, Fe(II)-chelating site (H1881), 2OG-interacting residues (R1896), and DNA-interacting loops.
This variant has been observed in COSMIC as a somatic mutation (27 entries) and reported in ClinVar with conflicting classifications (one VUS, one Pathogenic, single submitters with no expert panel review).
No variant-specific functional studies, de novo reports, segregation data, or case-control studies were identified for c.4354C>T in the reviewed literature.
No criteria match.
Met · 3
PVS1 StrongThis variant is a nonsense change (c.4354C>T, p.Arg1452Ter) predicted to result in premature termination and nonsense-mediated decay (NMD) in a gene where loss of function is an established germline disease mechanism. The variant is located in exon 10 of 11 and is not predicted to escape NMD. TET2 germline loss-of-function mutations are associated with an ALPS-like immune dysregulation syndrome with predisposition to hematologic malignancy (PMID:36066697, PMID:40031954). Under PMC6185798, nonsense variants in genes with established LoF disease mechanism qualify for PVS1 at full strength when not in the terminal exon. Details ▾Hide ▴
Evidence considered
- Nonsense variant (p.Arg1452Ter) in exon 10 of 11
- predicted to trigger NMD
- TET2 germline loss-of-function established as disease mechanism for ALPS-like syndrome and lymphoma predisposition
- PMID:40031954 reports heterozygous germline TET2 loss-of-function variants causing ALPS-like phenotype with lymphoma
- PMC6185798 PVS1 framework supports full strength for nonsense variants in LoF disease genes
Still missing
- No official CSPEC/VCEP for TET2
- relying on literature-based gene-disease association rather than expert panel confirmation
Sources
PM1 ModerateThe variant truncates the TET2 protein at position 1452, which lies within the catalytic domain (residues 1129-1936 as defined by PMID:24315485). The truncation removes the DSBH core and C-terminal catalytic machinery including Fe(II)-chelating residues (H1881), 2OG-interacting residues (R1896), and DNA-interacting loops. The catalytic domain is a well-characterized functional domain critical for TET2's 5-methylcytosine dioxygenase activity. Truncating variants that remove this domain abrogate TET2 enzymatic function. Details ▾Hide ▴
Evidence considered
- Variant truncates at residue 1452 within the catalytic domain (1129-1936)
- PMID:24315485 defines the catalytic domain structure and functionally critical residues
- Truncation removes DSBH core
- Fe(II)-chelating site
- and DNA-interacting loops
Sources
PM2 SupportingThis variant is present in gnomAD at extremely low allele frequency: v2.1 AF=1.28e-5 (0.00128%, 2/156592 alleles), v4.1 AF=9.67e-6 (0.00097%, 15/1551500 alleles), well below the 0.1% threshold for PM2. It is absent from gnomAD-Canada. No homozygotes have been observed in any population database. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=1.28e-5 (0.00128%)
- 2/156592 alleles
- 0 homozygotes
- gnomAD v4.1 AF=9.67e-6 (0.00097%)
- 15/1551500 alleles
- Absent from gnomAD-Canada v1.0
- All frequencies substantially below PM2 threshold of 0.1%
Sources
Not met · 14 · evaluated, threshold not reached
PS3 No variant-specific functional data or systematic range characterization covering position Arg1452 was identified in the literature. The functional studies reviewed (PMID:21057493, PMID:24315485) characterized TET2 catalytic activity and crystal structure but tested different residues and did not assess the effect of truncation at position 1452. OncoKB curation labels this variant as 'Likely Loss-of-function' based on the nonsense mechanism, not variant-specific experimental evidence. Without direct functional testing or systematic range characterization that includes this variant position, PS3 is not met. Details ▾Hide ▴
Evidence considered
- PMID:21057493 tested TET2 catalytic activity for specific missense mutations (H1302Y
- D1304A
- H1802R
- etc.) but did not test R1452*
- PMID:24315485 defined the TET2 catalytic domain structure (residues 1129-1936) but did not functionally assess truncation at residue 1452
- OncoKB 'Likely Loss-of-function' label is based on predicted truncation mechanism
- not experimental data
Still missing
- No variant-specific or systematic-range functional assay data available for position 1452
- Truncation at position 1452 falls within the catalytic domain but has not been experimentally characterized
Sources
PS4 The variant has been observed in gnomAD at extremely low frequency (v2.1: 2/156592; v4.1: 15/1551500 alleles) and reported in ClinVar with conflicting classifications (one VUS, one Pathogenic, single submitters only). COSMIC reports 27 somatic occurrences but these are not germline cases. No case-control study or statistically significant enrichment in affected individuals has been demonstrated. The PMID:36066697 paper describes germline TET2 disease but reports different variants (p.Gly93Ter, p.Asn598IlefsTer3, 4q24del), not c.4354C>T. Details ▾Hide ▴
Evidence considered
- Extremely low population frequency in gnomAD (v2.1 AF=0.00128%
- v4.1 AF=0.00097%)
- Conflicting ClinVar classifications (VUS and Pathogenic)
- no expert panel review
- COSMIC somatic occurrences (n=27) are not evidence of germline prevalence
Still missing
- No case-control data available
- No systematic comparison of variant frequency in cases vs controls
Sources
PP1 No co-segregation data is available for this variant. None of the reviewed publications report familial segregation analysis involving NM_001127208.2:c.4354C>T. Details ▾Hide ▴
Still missing
- No family segregation data available
PP3 Computational evidence does not support a deleterious effect for this variant. SpliceAI predicts no significant splice impact (max delta score = 0.16). BayesDel score is 0.558747 (borderline, not strongly pathogenic). REVEL and HCI prior scores are unavailable. There is no consensus from multiple in silico tools supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.16 (not significant)
- BayesDel = 0.559 (borderline
- not strongly pathogenic)
- REVEL not available for this variant
- No HCI prior available
Sources
spliceai ↗bayesdel
PP5 No reputable source has definitively classified this variant as pathogenic. ClinVar contains two single-submitter classifications (one VUS by GeneDx, one Pathogenic by Invitae) with no expert panel review. The conflicting classifications and absence of expert panel consensus do not meet PP5 requirements. Details ▾Hide ▴
Evidence considered
- ClinVar: 1 VUS (GeneDx SCV002008743) + 1 Pathogenic (Invitae SCV004531150)
- No expert panel review
- review status is 'criteria provided
- single submitter'
Still missing
- No expert panel consensus classification available
Sources
BA1 The maximum allele frequency in gnomAD is 1.28e-5 (0.00128%) in v2.1 and 9.67e-6 (0.00097%) in v4.1, both well below the BA1 threshold of 1% (and adjusting AF). The variant is too rare to be considered a common polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.00128% << BA1 threshold of 1%
- gnomAD v4.1 AF=0.00097% << BA1 threshold of 1%
Sources
BS1 The maximum allele frequency in gnomAD (0.00128% in v2.1, 0.00097% in v4.1) is well below the BS1 threshold of 0.3%. The variant is too rare in population databases to be considered benign. Details ▾Hide ▴
BS2 No homozygous individuals have been observed in any population database (gnomAD v2.1: 0 homozygotes out of 156592 alleles; gnomAD v4.1: 0 homozygotes out of 1551500 alleles). The variant is not observed in a homozygous state in healthy adults, so BS2 does not apply. Details ▾Hide ▴
Evidence considered
- Zero homozygotes observed in gnomAD across all populations
Sources
BS3 No functional studies demonstrate a benign effect for this variant. The reviewed functional literature (PMID:21057493, PMID:24315485) characterizes TET2 catalytic activity and structure but does not include R1452*. The evidence, though indirect, is consistent with loss of function (truncation of catalytic domain), not a benign effect. Details ▾Hide ▴
Evidence considered
- No in vitro or in vivo studies demonstrate normal function for R1452*
- Structure-function data are consistent with loss of catalytic domain
- not benign effect
Sources
BS4 No segregation data is available for this variant. No family studies demonstrate lack of co-segregation with disease. Details ▾Hide ▴
Still missing
- No family segregation data available
BP4 Computational evidence does not support a benign effect. BayesDel score is 0.559 (borderline, not clearly benign). SpliceAI shows no significant splice impact but this is neutral, not benign. REVEL is unavailable. No consensus from multiple in silico tools indicates a benign effect. Details ▾Hide ▴
Evidence considered
- BayesDel = 0.559 (not indicative of benign effect)
- SpliceAI max delta = 0.16 (neutral
- not evidence for or against pathogenicity)
Sources
spliceai ↗bayesdel
BP5 No observation of this variant in a case with an alternate molecular basis for disease is available. The required evidence (variant found in individual with a different confirmed genetic cause for the same phenotype) is absent. Details ▾Hide ▴
Still missing
- No data on co-occurrence with alternative molecular diagnoses
BP6 This variant is not classified as Benign or Likely Benign by a reputable source. ClinVar shows classifications of VUS and Pathogenic, not benign. BP6 requires a benign classification from a reputable source with evidence sharing. Details ▾Hide ▴
Evidence considered
- ClinVar classifications: VUS (GeneDx) and Pathogenic (Invitae)
- not benign
Sources
PS5 No reputable source has recently reported this variant as pathogenic. ClinVar contains two single-submitter classifications (one VUS, one Pathogenic) with no expert panel review. This does not satisfy the PS5 requirement for a recently established pathogenic classification from a reputable source. Details ▾Hide ▴
Evidence considered
- ClinVar shows single-submitter pathogenic classification (SCV004531150) with no expert panel concurrence
Still missing
- No expert panel or multi-institutional consensus classification available
Sources
Not assessed · 4 · no assessment recorded
PS2 No de novo report was identified for NM_001127208.2:c.4354C>T. The available literature describes de novo occurrence of different TET2 variants (e.g., p.Gly93Ter in PMID:36066697) but not this specific variant. Without a confirmed de novo observation, PS2 cannot be applied. Details ▾Hide ▴
Still missing
- No de novo testing data available for this variant
PM6 No de novo report was identified for NM_001127208.2:c.4354C>T in the reviewed literature. The PMID:36066697 paper describes a different variant (p.Gly93Ter) as de novo but does not report de novo occurrence of c.4354C>T. Without a confirmed de novo observation of this specific variant, PM6 cannot be applied. Details ▾Hide ▴
Still missing
- No de novo testing data or parental genotyping available for this variant
PP4 Insufficient phenotype data is available for patients carrying this variant. ClinVar submissions list conditions as 'Not Provided' (GeneDx) or provide no condition labels (Invitae). Without a specific patient phenotype that matches the TET2-associated disease spectrum, PP4 cannot be assessed. Details ▾Hide ▴
Still missing
- No patient phenotype data available for individuals carrying this variant
Sources
BP2 No data is available regarding observation of this variant in trans with a known pathogenic variant. This information would require clinical testing data not present in the case materials. Details ▾Hide ▴
Still missing
- No data on trans configurations with pathogenic variants
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to missense variants where the same amino acid change has been observed as pathogenic via a different nucleotide change. This variant is a nonsense (stop-gain) change, not a missense. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 applies to missense variants at the same residue where a different pathogenic missense change has been observed. This variant is a nonsense (stop-gain), and no same-residue comparator candidates were identified by the automated PM5 candidate search. Details ▾Hide ▴
Evidence considered
- pm5_candidates.json reports no same-residue candidates found
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This variant is a nonsense (stop-gain), not a missense variant. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This variant is itself a truncating (nonsense) variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) or intronic variants without predicted splice impact at non-conserved positions. This variant is a nonsense (stop-gain) variant, not synonymous or intronic. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- TET2
- Transcript
- NM_001127208.2
- Coding (HGVS c.)
- NM_001127208.2:c.4354C>T
- Protein (HGVS p.)
- NP_001120680.1:p.(Arg1452Ter)
- GRCh38
- chr4:105272735 C>T
- GRCh37
- chr4:106193892 C>T
- ClinVar
- 1318626
- COSMIC
- COSV54398405
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
15 / 1,551,500 alleles
AF 9.67e-06 · 0 homozygotes · FAF 1.56e-05
gnomAD v2.1
2 / 156,592 alleles
AF 1.28e-05 · 0 homozygotes · FAF 1.34e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 9.7e-06 · 15 / 1,551,500 alleles · 0 hom · FAF 1.6e-05
| Admixed American3 / 50,992 | 5.9e-05 |
| South Asian1 / 84,048 | 1.2e-05 |
| European (non-Finnish)11 / 1,146,940 | 9.6e-06 |
0 alternate alleles recorded in 7 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.3e-05 · 2 / 156,592 alleles · 0 hom · FAF 1.3e-05
| Admixed American2 / 24,680 | 8.1e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 9.66806e-06; MAF= 0.00097%, 15/1551500 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.88328e-05; MAF= 0.00588%, 3/50992 alleles, homozygotes = 0); grpmax FAF= 1.561e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.2772e-05; MAF= 0.00128%, 2/156592 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.10373e-05; MAF= 0.00810%, 2/24680 alleles, homozygotes = 0); grpmax FAF= 1.341e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001086484137331595, 2/18408 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.559
How the predictions were used
PP3 Computational evidence does not support a deleterious effect for this variant. SpliceAI predicts no significant splice impact (max delta score = 0.16). BayesDel score is 0.558747 (borderline, not strongly pathogenic). REVEL and HCI prior scores are unavailable. There is no consensus from multiple in silico tools supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.16 (not significant)
- BayesDel = 0.559 (borderline
- not strongly pathogenic)
- REVEL not available for this variant
- No HCI prior available
Sources
spliceai ↗bayesdel
BP4 Computational evidence does not support a benign effect. BayesDel score is 0.559 (borderline, not clearly benign). SpliceAI shows no significant splice impact but this is neutral, not benign. REVEL is unavailable. No consensus from multiple in silico tools indicates a benign effect. Details ▾Hide ▴
Evidence considered
- BayesDel = 0.559 (not indicative of benign effect)
- SpliceAI max delta = 0.16 (neutral
- not evidence for or against pathogenicity)
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous (silent) or intronic variants without predicted splice impact at non-conserved positions. This variant is a nonsense (stop-gain) variant, not synonymous or intronic. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.16). BayesDel score = 0.558747.
3 paper records listed. 3 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 catalytic activity by expressing wild-type and mutant murine Tet2 in HEK293T cells, confirming that Tet2 converts 5-methylcytosine to 5-hydroxymethylcytosine and that mutations in Fe(II)-chelating and 2OG-interacting residues abolish enzymatic activity. Specific mutations tested include H1302Y, D1304A, H1802R, H1802Q, P1287S, W1211R, C1834D, and R1817S/M.→ 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 Full text: Results section describing transient transfection and immunocytochemistry assays
Context Transient transfection of HEK293T cells with Myc-tagged murine Tet2 constructs; 5-hmC and 5-mC detection by immunocytochemistry and dot blot assays
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PMID 24315485 ↗Crystal structure of TET2-DNA complex: insight into TET-mediated 5mC oxidation.Presents the crystal structure of human TET2 catalytic domain (residues 1129-1936) bound to methylated DNA at 2.02A resolution. Identifies key catalytic residues including Fe(II)-chelating residues H1382, D1384, H1881 and NOG-interacting residues R1261, H1416, R1896, S1898. Defines domain boundaries including the low-complexity insert region (residues 1464-1843).→ PM1 Does not name this variant
Source detail
The structure shows that two zinc fingers bring the Cys-rich and DSBH domains together to form a compact catalytic domain.
Location Results: Structure Determination and Overall Structure of TET2-DNA Complex sections
Context X-ray crystallography of human TET2 (1129-1936) with 12bp DNA and NOG; dot blot and LC-MS/MS functional assays in HEK293T cells
-
PMID 36066697 ↗Novel Germline TET2 Mutations in Two Unrelated Patients with Autoimmune Lymphoproliferative Syndrome-Like Phenotype and Hematologic Malignancy.López-Nevado M et al. · 2023 JanReports two unrelated ALPS-like patients with novel germline TET2 mutations: P1 (compound heterozygous for c.277G>T/p.Gly93Ter and c.1793delA/p.Asn598IlefsTer3, biallelic) and P2 (heterozygous 4q24 deletion affecting TET2, monoallelic). Both presented with T-cell lymphoma, chronic lymphoproliferation, and immune dysregulation. Functional studies confirmed absent TET2 expression and global DNA hypermethylation in the biallelic patient.→ PVS1 Does not name this variant
Source detail
Two novel previously unreported heterozygous germline variants in TET2 (c.277G>T, p.Gly93Ter and c.1793delA, p.Asn598IlefsTer3) were detected in WES analysis and confirmed by Sanger sequencing
Location Results: Identification of Novel Germline LOF Mutations section and Table 2
Context Whole exome sequencing, targeted NGS gene panel, Sanger sequencing, qPCR, Western blot, global DNA methylation assay, flow cytometry immunophenotyping
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
15 / 1,551,500 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.160
Open source ↗
ClinVar
1 Uncertain significance · 1 Pathogenic
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/variation/1318626/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/4-106193892-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr4-105272735-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/4-105272735-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001127208.2%3Ac.4…
- OncoKB ↗www.oncokb.org/gene/TET2/R1452*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=194816307
- 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= 9.66806e-06; MAF= 0.00097%, 15/1551500 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.88328e-05; MAF= 0.00588%, 3/50992 alleles, homozygotes = 0); grpmax FAF= 1.561e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.2772e-05; MAF= 0.00128%, 2/156592 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.10373e-05; MAF= 0.00810%, 2/24680 alleles, homozygotes = 0); grpmax FAF= 1.341e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001086484137331595, 2/18408 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Pathogenic (1 clinical laboratory). (ClinVarID = 1318626)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.16). BayesDel score = 0.558747.
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; COSV54398405, n = 27 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.