About TET2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TET2 c.5481del, p.(Lys1827AsnfsTer6)
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
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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
PVS1Strong
PVS1 · strong
NM_001127208.2:c.5481del is a frameshift deletion in exon 11 (the terminal exon) of TET2, predicted to cause p.Lys1827AsnfsTer6, a premature termination codon truncating the protein from 2003 to 1832 amino acids with loss of approximately 176 C-terminal residues. TET2 loss of function is a well-established germline disease mechanism (ALPS-like phenotype, hematologic malignancy predisposition). Under PMC6185798 (ClinGen SVI PVS1 recommendations), a null variant in a gene with established LOF disease mechanism qualifies for PVS1 at very strong level; however, because the variant resides in the terminal exon and is predicted to escape nonsense-mediated decay, the strength is downgraded to PVS1_Strong.
PM2Moderate
PM2 · moderate
NM_001127208.2:c.5481del is entirely absent from gnomAD population databases: absent from v2.1 exomes, v4.1 exomes (0/1,399,432 alleles) and genomes (0/152,304 alleles), combined 0/1,551,736 alleles (AF=0.0000%). This meets the PM2 threshold for extremely low or absent population frequency (<0.1%).
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, PM2 moderate; combination = 1 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
0 / 1,551,736 alleles
gnomAD v4.1: 0 / 1,551,736 alleles. Recorded AF 0. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. 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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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 · 16 not met · 2 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
PVS1_Strong: NM_001127208.2:c.5481del is a frameshift deletion (p.Lys1827AsnfsTer6) in TET2, a gene where germline loss of function is an established disease mechanism for ALPS-like immunodeficiency and hematologic malignancy predisposition. The variant resides in the terminal exon (exon 11/11) and is predicted to escape nonsense-mediated decay; strength is downgraded from PVS1 to PVS1_Strong per PMC6185798.
PM2: Variant is entirely absent from gnomAD v4.1 (0/1,551,736 alleles, AF=0.0000%) and gnomAD v2.1, meeting the PM2 threshold for extremely low population frequency.
No additional pathogenic or benign criteria were met. PS3 (functional evidence) and BS3 (benign functional evidence) could not be assessed as no variant-specific functional studies for NM_001127208.2:c.5481del were identified in the reviewed literature (PMID:21057493, PMID:24315485).
No criteria match.
Met · 2
PVS1 StrongNM_001127208.2:c.5481del is a frameshift deletion in exon 11 (the terminal exon) of TET2, predicted to cause p.Lys1827AsnfsTer6, a premature termination codon truncating the protein from 2003 to 1832 amino acids with loss of approximately 176 C-terminal residues. TET2 loss of function is a well-established germline disease mechanism (ALPS-like phenotype, hematologic malignancy predisposition). Under PMC6185798 (ClinGen SVI PVS1 recommendations), a null variant in a gene with established LOF disease mechanism qualifies for PVS1 at very strong level; however, because the variant resides in the terminal exon and is predicted to escape nonsense-mediated decay, the strength is downgraded to PVS1_Strong. Details ▾Hide ▴
Evidence considered
- Frameshift deletion c.5481del predicted to cause p.Lys1827AsnfsTer6
- Variant in terminal exon (exon 11/11)
- NMD predicted to escape (PMC6185798 downgrade)
- TET2 germline LOF is a known disease mechanism (PMID:36066697
- PMID:40031954)
- No ClinGen CSPEC/VCEP framework available
- generic PVS1 fallback applied
Still missing
- Confirm transcript NM_001127208.2 relevance for clinical reporting
- NM_001127208.3 is the current version
- Assess whether the lost C-terminal residues (1832-2003) include critical functional domains that would determine whether full PVS1_VeryStrong is appropriate despite NMD escape
Sources
PM2 ModerateNM_001127208.2:c.5481del is entirely absent from gnomAD population databases: absent from v2.1 exomes, v4.1 exomes (0/1,399,432 alleles) and genomes (0/152,304 alleles), combined 0/1,551,736 alleles (AF=0.0000%). This meets the PM2 threshold for extremely low or absent population frequency (<0.1%). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 0/1
- 551
- 736 total alleles (AF=0.0000%)
- gnomAD v2.1: absent
- gnomAD-Canada v1.0: absent
- Highest subpopulation AF: African/African American 0/73
- 164 (AF=0.0000%)
Sources
Not met · 16 · evaluated, threshold not reached
PS2 No de novo evidence for this variant was identified. Neither the literature search nor ClinVar submissions report a de novo occurrence of NM_001127208.2:c.5481del. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar (variant absent from ClinVar)
- No de novo reports in any reviewed publication
Still missing
- Parental testing results for the proband
- if available
- could allow assessment of de novo status
PS4 The variant is entirely absent from gnomAD v2.1, gnomAD v4.1 (0/1,551,736 alleles), and gnomAD-Canada. No case-control studies or cohort enrichment data are available to demonstrate a statistically significant excess in affected individuals. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1 (0/1
- 551
- 736 alleles
- AF=0%)
- Absent from gnomAD-Canada v1.0
Still missing
- Case-control or cohort enrichment data would be needed to meet PS4 thresholds
Sources
PM1 Residue 1827 does not lie in a statistically significant cancer hotspot. While the variant falls within the TET2 catalytic domain (C-terminal DSBH domain, residues ~1129-1936), absence of a recognized mutational hotspot at this position precludes application of PM1. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots analysis: exact variant not listed
- residue not significant
- No statistically significant mutational hotspot at codon 1827
PM6 No de novo evidence was identified. PM6 requires a confirmed de novo occurrence with both maternity and paternity confirmed. No such reports exist for this variant in ClinVar or the reviewed literature. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar (variant absent from ClinVar entirely)
- No de novo reports in reviewed publications
Still missing
- Parental testing would be required to assess de novo status
PP1 No segregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members. Details ▾Hide ▴
Evidence considered
- No family segregation studies available
Still missing
- Family segregation data would be needed to apply PP1
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splice impact (max delta score = 0.00). REVEL and BayesDel scores are not available for this non-SNV variant. No additional computational evidence supports pathogenicity for this frameshift deletion. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta score = 0.00 (no predicted splice impact)
- REVEL: not applicable (not an SNV)
- BayesDel: not applicable (not an SNV)
- HCI Prior: gene not supported
Sources
PP4 No patient phenotype or family history data are available for this variant. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The proband's clinical presentation is unknown. Details ▾Hide ▴
Evidence considered
- No proband phenotype or family history data available
Still missing
- Clinical phenotype and family history of the proband are needed to assess PP4
PP5 No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar entirely, and no expert panel or clinical laboratory has reported it. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar: no classifications submitted by any laboratory
Sources
BA1 The variant is entirely absent from gnomAD (0/1,551,736 alleles, AF=0.0000%), far below the BA1 threshold of >1% population frequency. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF=0.0000%
- 0/1
- 551
- 736 alleles
- All subpopulations: AF=0.0000%
Sources
BS1 The variant is entirely absent from gnomAD (0/1,551,736 alleles, AF=0.0000%), far below the BS1 threshold of >0.3% population frequency. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF=0.0000%
- 0/1
- 551
- 736 alleles
- Highest subpopulation AF: 0.0000%
Sources
BS2 No homozygous observations have been reported in any population database. BS2 requires observation in a healthy adult individual in a homozygous state, or in trans with a known pathogenic variant, with full penetrance expected at an early age. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 0 homozygotes observed
- No observations in trans with a pathogenic variant
Sources
BS4 No evidence of lack of segregation is available. BS4 requires observation of the variant in a family member who does not have the disease phenotype or lack of cosegregation in multiple affected family members. Details ▾Hide ▴
Evidence considered
- No family segregation data available
Still missing
- Family segregation data would be needed to assess BS4
BP2 No observation of this variant in trans with a known pathogenic variant has been reported. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern. Details ▾Hide ▴
Evidence considered
- No observations in trans or cis with a pathogenic TET2 variant
BP4 Multiple lines of computational evidence do not support a benign impact. SpliceAI predicts no splice effect (max delta = 0.00), but this is neutral rather than positively benign. No other in silico scores are available for this non-SNV variant. BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00 (neutral
- not positively benign for a coding frameshift)
- No additional in silico predictors applicable to non-SNV variants
Sources
BP5 No alternative molecular basis for disease has been identified in this case. BP5 requires a variant found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis reported
BP6 No reputable source has classified this variant as benign. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Not assessed · 2 · no assessment recorded
PS3 No variant-specific functional studies for NM_001127208.2:c.5481del (p.Lys1827AsnfsTer6) were identified. Two papers (PMID:21057493, PMID:24315485) report general TET2 functional characterization but neither mentions this specific variant. OncoKB classifies the variant as Likely Oncogenic in a somatic context based on general TET2 LOF biology, not variant-specific functional assays. Details ▾Hide ▴
Evidence considered
- OncoKB: Likely Oncogenic / Likely Loss-of-function (somatic context
- not germline PS3-grade evidence)
- No variant-specific functional assays identified in reviewed publications
Still missing
- Variant-specific functional studies (e.g.
- enzymatic activity assays
- 5hmC quantification) would be needed to apply PS3
- OncoKB somatic annotation does not constitute germline PS3 evidence
Sources
BS3 No variant-specific functional studies demonstrating a benign effect were identified. The two reviewed publications (PMID:21057493, PMID:24315485) report general TET2 structural and functional characterization but do not mention NM_001127208.2:c.5481del. BS3 cannot be assessed without variant-level functional data showing no deleterious impact. Details ▾Hide ▴
Evidence considered
- No variant-specific functional assays identified
- OncoKB annotation indicates likely loss-of-function (somatic context)
- which is inconsistent with a benign functional effect
Still missing
- Variant-specific functional studies demonstrating normal TET2 activity would be needed to apply BS3
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies when the variant is an amino acid change at the same position as a known pathogenic missense variant. NM_001127208.2:c.5481del is a frameshift deletion, not a missense variant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 addresses protein length changes from in-frame deletions/insertions or stop-loss variants. NM_001127208.2:c.5481del is a frameshift deletion causing a premature termination codon; the null variant mechanism is already assessed under PVS1. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 requires a known pathogenic missense variant at the same amino acid residue. NM_001127208.2:c.5481del is a frameshift deletion, not a missense change. The PM5 candidates analysis confirmed that classic same-residue PM5 semantics cannot be applied to this variant. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvesting: not eligible (frameshift
- not a missense variant)
Sources
pm5_candidates
PP2 N/APP2 applies specifically to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. NM_001127208.2:c.5481del is a frameshift deletion, not a missense variant. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in a gene where a different pathogenic missense change at the same residue has been established. NM_001127208.2:c.5481del is a frameshift deletion, not a missense variant. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions without known function. NM_001127208.2:c.5481del is a frameshift deletion, not an in-frame indel. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_001127208.2:c.5481del is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not applicable because PS1 (the prerequisite for PS5) does not apply to this frameshift deletion variant. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- TET2
- Transcript
- NM_001127208.2
- Coding (HGVS c.)
- NM_001127208.2:c.5481del
- Protein (HGVS p.)
- NP_001120680.1:p.(Lys1827AsnfsTer6)
- GRCh38
- chr4:105275990 AG>A
- GRCh37
- chr4:106197147 AG>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
0 / 1,551,736 alleles
AF 0 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0 · 0 / 1,551,736 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1551736 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73164 alleles, homozygotes = 0).
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
- Not available
How the predictions were used
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splice impact (max delta score = 0.00). REVEL and BayesDel scores are not available for this non-SNV variant. No additional computational evidence supports pathogenicity for this frameshift deletion. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta score = 0.00 (no predicted splice impact)
- REVEL: not applicable (not an SNV)
- BayesDel: not applicable (not an SNV)
- HCI Prior: gene not supported
Sources
BP4 Multiple lines of computational evidence do not support a benign impact. SpliceAI predicts no splice effect (max delta = 0.00), but this is neutral rather than positively benign. No other in silico scores are available for this non-SNV variant. BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00 (neutral
- not positively benign for a coding frameshift)
- No additional in silico predictors applicable to non-SNV variants
Sources
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_001127208.2:c.5481del is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
2 paper records 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 21057493 ↗Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2.Characterizes TET2 as a 5-methylcytosine dioxygenase that converts 5mC to 5hmC. Reports functional effects of various TET2 missense mutations (H1302Y, D1304A, H1802R, H1802Q, P1287S, W1211R, C1834D, R1817S/M) on catalytic activity in HEK293T cells. NM_001127208.2:c.5481del (p.Lys1827AsnfsTer6) was not identified in this paper.Does not name this variant
-
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 2.02 A resolution. Identifies key catalytic residues (H1382, D1384, H1881), DNA-interacting residues, and zinc-coordinating residues. Reports functional characterization of patient-derived mutations (R1896M, R1261G, S1898F) by dot blot and LC-MS/MS. NM_001127208.2:c.5481del (p.Lys1827AsnfsTer6) was not identified in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
0 / 1,551,736 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
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.5481del
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/4-106197147-AG-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr4-105275990-AG-A?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/4-105275990-AG-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001127208.2%3Ac.5…
- OncoKB ↗www.oncokb.org/gene/TET2/K1827Nfs*6
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=TET2+c.5481del
- 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= 0; MAF= 0.00000%, 0/1551736 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73164 alleles, homozygotes = 0).
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 = 0.00).
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.