About TET2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TET2 c.5666C>T, p.(Pro1889Leu)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is extremely rare in population databases. It is absent from gnomAD v2.1 (0/155,736 alleles) and gnomAD-Canada (0 alleles). In gnomAD v4.1, it is observed at an allele frequency of 6.45×10⁻⁷ (1/1,551,522 alleles), well below the 0.1% PM2 threshold.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest this variant has no significant impact on the gene product. REVEL score is 0.398 (below the pathogenic threshold), BayesDel score is -0.091 (benign-leaning), and SpliceAI predicts no splice alteration (max delta = 0.00). Three independent in silico tools converge on a neutral or benign prediction.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
1 / 1,551,522 alleles
gnomAD v4.1: 1 / 1,551,522 alleles. Recorded AF 6.44528e-07. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/155736 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/7876 alleles, homozygotes = 0).
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.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TET2, a tumor suppressor and DNA demethylase, is frequently mutated in hematologic malignancies.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
4 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV54425537, n = 4 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: 2 met · 11 not met · 10 not assessed · 3 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.5666C>T (p.Pro1889Leu) is a missense variant in exon 11 of TET2.
This variant is extremely rare in population databases: absent from gnomAD v2.1 (0/155,736 alleles) and present at an allele frequency of 6.45×10⁻⁷ in gnomAD v4.1 (1/1,551,522 alleles), well below the 0.1% threshold for PM2 (supporting).
Multiple in silico predictors suggest the variant is benign: REVEL score 0.398, BayesDel score -0.091, and SpliceAI predicts no splice impact (max delta = 0.00), meeting BP4 (supporting benign).
The variant is absent from ClinVar and has no published functional data. No papers were identified that mention NM_001127208.2:c.5666C>T specifically.
The variant has been observed in COSMIC (COSV54425537, n=4) as a somatic finding in cancer but lacks germline functional characterization.
PVS1 is not applicable (missense variant, not a null variant). PS1, PM5, and BP7 are not applicable due to lack of same-residue comparators or variant type mismatch.
No criteria match.
Met · 2
PM2 SupportingThis variant is extremely rare in population databases. It is absent from gnomAD v2.1 (0/155,736 alleles) and gnomAD-Canada (0 alleles). In gnomAD v4.1, it is observed at an allele frequency of 6.45×10⁻⁷ (1/1,551,522 alleles), well below the 0.1% PM2 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0/155
- 736 alleles (0.0%)
- gnomAD v4.1: 1/1
- 551
- 522 alleles (AF=6.45e-07)
- gnomAD-Canada: absent. All far below 0.1% PM2 threshold.
Sources
BP4 SupportingMultiple lines of computational evidence suggest this variant has no significant impact on the gene product. REVEL score is 0.398 (below the pathogenic threshold), BayesDel score is -0.091 (benign-leaning), and SpliceAI predicts no splice alteration (max delta = 0.00). Three independent in silico tools converge on a neutral or benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL 0.398 (<0.5
- benign-leaning)
- BayesDel -0.091 (benign-leaning)
- SpliceAI max delta 0.00 (no predicted splice impact).
Sources
Not met · 11 · evaluated, threshold not reached
PS1 No previously established pathogenic variant at the same amino acid position (Pro1889) has been identified in ClinVar. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- ClinVar contains no entries for any variant at Pro1889 in TET2
- no same-amino-acid pathogenic comparator exists.
Sources
PS3 No well-established in vitro or in vivo functional studies have been identified for this variant. In silico predictors are inconsistent: REVEL score is 0.398 (below 0.5 pathogenicity threshold) and BayesDel score is -0.091 (benign-leaning). OncoKB classifies this variant as having unknown oncogenic effect with no variant-specific curated functional evidence. Details ▾Hide ▴
Evidence considered
- REVEL 0.398 (below pathogenic threshold)
- BayesDel -0.091 (benign-leaning)
- OncoKB reports unknown oncogenic effect with no variant-specific functional studies.
Still missing
- No variant-specific functional assays (enzymatic activity
- methylation
- or protein interaction studies) available.
Sources
PM1 This variant does not lie in a statistically significant mutational hotspot. The variant (Pro1889Leu) is located in the C-terminal region of TET2 but has not been identified within a recognized functional domain where pathogenic missense variants cluster without benign variation. Details ▾Hide ▴
Evidence considered
- Hotspot analysis reports variant is not in a statistically significant hotspot
- no CSPEC/VCEP domain-level PM1 guidance for TET2.
PP2 TET2 is not recognized as a gene with a low rate of benign missense variation. TET2 is frequently mutated in hematologic malignancies and population databases, and the established germline disease mechanism involves loss-of-function variants (including both truncating and missense). PP2 is not applicable in this context. Details ▾Hide ▴
Evidence considered
- TET2 has high background missense variation
- germline disease mechanism is loss-of-function
- not specifically missense-driven.
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.398 (below the 0.5 pathogenic threshold), BayesDel score is -0.091 (benign-leaning), and SpliceAI predicts no splice impact (max delta = 0.00). No HCI prior score is available for TET2. Details ▾Hide ▴
Evidence considered
- REVEL 0.398 (<0.5)
- BayesDel -0.091 (negative)
- SpliceAI max delta 0.00
- HCI prior not available for TET2.
Sources
PP5 No reputable source (ClinVar, published literature) has reported this variant as pathogenic. The variant is absent from ClinVar, and OncoKB classifies it as having unknown oncogenic effect. Details ▾Hide ▴
BA1 This variant has an allele frequency of 6.45×10⁻⁷ (0.00006%) in gnomAD v4.1, far below the 1% BA1 threshold. It does not meet the stand-alone benign population frequency criterion. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 overall AF = 6.45e-07
- gnomAD v2.1 AF = 0.0. Both far below 1% BA1 threshold.
Sources
BS1 This variant has an allele frequency of 6.45×10⁻⁷ in gnomAD v4.1, far below the 0.3% BS1 threshold. The variant is too rare to meet BS1. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF = 6.45e-07
- gnomAD v2.1 AF = 0.0. Both far below 0.3% BS1 threshold.
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing have been identified for this variant. Computational predictions alone (BayesDel -0.091, REVEL 0.398) are insufficient to meet BS3. Details ▾Hide ▴
Evidence considered
- BayesDel -0.091 and REVEL 0.398 are benign-leaning but are computational predictors
- not established functional assays
- no variant-specific functional studies available.
Still missing
- No variant-specific functional studies demonstrating neutral effect.
Sources
bayesdelrevel
BP1 While TET2 germline disease is associated with loss-of-function variants, the published literature describes both truncating and missense germline variants (PMID:36066697, PMID:40031954). There is insufficient evidence that TET2 disease is primarily caused by truncating variants to the exclusion of missense variants. BP1 cannot be applied. Details ▾Hide ▴
Evidence considered
- Germline TET2 literature (PMID:36066697
- PMID:40031954) reports both truncating and missense variants
- insufficient evidence that truncating variants are the predominant disease mechanism.
BP6 No reputable source has reported this variant as benign. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no source classifies it as benign.
Sources
Not assessed · 10 · no assessment recorded
PS2 No de novo data (with confirmed paternity and maternity) are available for this variant. Details ▾Hide ▴
Still missing
- No family studies or de novo testing data available.
PS4 No case-control data comparing variant prevalence in affected individuals versus controls are available. Details ▾Hide ▴
Still missing
- No case-control study data available.
PM6 No de novo data (without paternity/maternity confirmation) are available for this variant. Details ▾Hide ▴
Still missing
- No de novo reports for this variant.
PP1 No cosegregation data in affected family members are available. Details ▾Hide ▴
Still missing
- No family segregation studies available.
PP4 No patient phenotype or family history data are available to assess specificity for TET2-related disease. Details ▾Hide ▴
Still missing
- No clinical phenotype or family history data provided.
BS2 No data are available regarding observation of this variant in healthy adults at an age when fully penetrant disease would be expected. Details ▾Hide ▴
Still missing
- No data on healthy adult carriers.
BS4 No segregation data in affected family members are available to assess lack of cosegregation with disease. Details ▾Hide ▴
Still missing
- No family segregation studies available.
BP2 No data are available regarding observation of this variant in trans with a known pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
- No trans-phase data available.
BP5 No data are available regarding an alternate molecular basis for disease in a case carrying this variant. Details ▾Hide ▴
Still missing
- No patient-level data with alternate molecular diagnoses.
PS5 No data are available regarding an alternate molecular basis for disease in a patient carrying this variant. Details ▾Hide ▴
Still missing
- No patient-level clinical or molecular data available.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Pro1889Leu). It does not fall into the ClinGen SVI PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). Generic PVS1 framework assessment is not applicable. Details ▾Hide ▴
Evidence considered
- Missense substitution c.5666C>T results in p.Pro1889Leu
- variant does not meet any null-variant criteria for PVS1 consideration.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM5 N/ANo same-residue (Pro1889) comparator variants classified as pathogenic were identified in ClinVar. PM5 candidate harvesting returned zero candidates. Details ▾Hide ▴
Evidence considered
- PM5 candidate scan found no pathogenic variants at Pro1889 with a different amino acid substitution.
Sources
pm5_candidates
BP7 N/AThis is a missense variant (c.5666C>T, p.Pro1889Leu), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- BP7 is only applicable to synonymous and deep intronic variants.
Identifiers
- Gene
- TET2
- Transcript
- NM_001127208.2
- Coding (HGVS c.)
- NM_001127208.2:c.5666C>T
- Protein (HGVS p.)
- NP_001120680.1:p.(Pro1889Leu)
- GRCh38
- chr4:105276176 C>T
- GRCh37
- chr4:106197333 C>T
- COSMIC
- COSV54425537
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
1 / 1,551,522 alleles
AF 6.45e-07 · 0 homozygotes
gnomAD v2.1
0 / 155,736 alleles
AF 0 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.4e-07 · 1 / 1,551,522 alleles · 0 hom
| European (non-Finnish)1 / 1,146,948 | 8.7e-07 |
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.
gnomAD v2.1
AF 0 · 0 / 155,736 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= 6.44528e-07; MAF= 0.00006%, 1/1551522 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.71879e-07; MAF= 0.00009%, 1/1146948 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/155736 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/7876 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.398
- BayesDel
- -0.091
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest this variant has no significant impact on the gene product. REVEL score is 0.398 (below the pathogenic threshold), BayesDel score is -0.091 (benign-leaning), and SpliceAI predicts no splice alteration (max delta = 0.00). Three independent in silico tools converge on a neutral or benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL 0.398 (<0.5
- benign-leaning)
- BayesDel -0.091 (benign-leaning)
- SpliceAI max delta 0.00 (no predicted splice impact).
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.398 (below the 0.5 pathogenic threshold), BayesDel score is -0.091 (benign-leaning), and SpliceAI predicts no splice impact (max delta = 0.00). No HCI prior score is available for TET2. Details ▾Hide ▴
Evidence considered
- REVEL 0.398 (<0.5)
- BayesDel -0.091 (negative)
- SpliceAI max delta 0.00
- HCI prior not available for TET2.
Sources
BP7 N/AThis is a missense variant (c.5666C>T, p.Pro1889Leu), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- BP7 is only applicable to synonymous and deep intronic variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.398. BayesDel score = -0.0914083.
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
1 / 1,551,522 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.5666C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/4-106197333-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr4-105276176-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/4-105276176-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001127208.2%3Ac.5…
- OncoKB ↗www.oncokb.org/gene/TET2/P1889L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=194817548
- 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= 6.44528e-07; MAF= 0.00006%, 1/1551522 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.71879e-07; MAF= 0.00009%, 1/1146948 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/155736 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/7876 alleles, homozygotes = 0).
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). REVEL score = 0.398. BayesDel score = -0.0914083.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TET2, a tumor suppressor and DNA demethylase, is frequently mutated in hematologic malignancies.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54425537, n = 4 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.