About TET2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TET2 c.4555G>A, p.(Gly1519Arg)
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 present at extremely low frequency in population databases: gnomAD v2.1 AF 0.00623% (9/144,414 alleles), gnomAD v4.1 AF 0.00416% (64/1,537,566 alleles), both well below the 0.1% PM2 threshold. Absent from gnomAD-Canada. No homozygotes observed. Highest subpopulation AF is 0.050% (Remaining/Middle Eastern), still below the 0.1% cutoff.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on gene product. REVEL score 0.272 is well below the 0.5 threshold for predicted deleteriousness. BayesDel score -0.267 falls in the benign range. SpliceAI predicts no splice alteration (max delta 0.00). Three independent in silico predictors consistently suggest a benign effect.
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
64 / 1,537,566 alleles
gnomAD v4.1: 64 / 1,537,566 alleles. Recorded AF 4.16242e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.23208e-05; MAF= 0.00623%, 9/144414 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000504032; MAF= 0.05040%, 2/3968 alleles, homozygotes = 0); grpmax FAF= 1.557e-05.
gnomAD-Canada
Not available in 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. ClinVar API review status: criteria provided, single submitter.
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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV113391840, n = 1 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: 2 met · 21 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
This variant is present at extremely low frequency in population databases, with gnomAD v2.1 allele frequency of 0.006% and v4.1 allele frequency of 0.004%, both below the 0.1% threshold for PM2 at supporting strength.
Multiple in silico predictors consistently suggest a benign impact: REVEL score 0.272 (below 0.5 threshold), BayesDel score -0.267 (benign range), and SpliceAI max delta 0.00 (no predicted splice alteration), meeting BP4 at supporting benign strength.
No variant-specific functional studies, de novo observations, segregation data, case-control data, or pathogenic ClinVar classifications were identified. The variant is a missense change (p.Gly1519Arg) outside of any established mutational hotspot or critical functional domain.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and insufficient for classification beyond Uncertain significance.
No criteria match.
Met · 2
PM2 SupportingThis variant is present at extremely low frequency in population databases: gnomAD v2.1 AF 0.00623% (9/144,414 alleles), gnomAD v4.1 AF 0.00416% (64/1,537,566 alleles), both well below the 0.1% PM2 threshold. Absent from gnomAD-Canada. No homozygotes observed. Highest subpopulation AF is 0.050% (Remaining/Middle Eastern), still below the 0.1% cutoff. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=6.23e-05 (9/144
- 414)
- 0 homozygotes
- grpmax FAF=1.56e-05. gnomAD v4.1: AF=4.16e-05 (64/1
- 537
- 566)
- grpmax FAF=1.38e-04. Both below PM2 threshold of 0.1%.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product. REVEL score 0.272 is well below the 0.5 threshold for predicted deleteriousness. BayesDel score -0.267 falls in the benign range. SpliceAI predicts no splice alteration (max delta 0.00). Three independent in silico predictors consistently suggest a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.272 (<0.5
- benign). BayesDel -0.267 (negative
- benign range). SpliceAI max delta 0.00 (no predicted splice impact). Three concordant benign predictions.
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No evidence of a different nucleotide change at amino acid position 1519 having been previously established as pathogenic. No ClinVar or literature reports of an alternate nucleotide substitution producing p.Gly1519Arg with a pathogenic classification. Details ▾Hide ▴
Evidence considered
- ClinVar VCV3714180 is the only submission at this residue (VUS
- single submitter)
- PM5 candidate search returned no same-residue comparator variants.
Still missing
- No alternate nucleotide changes at codon 1519 identified in ClinVar.
Sources
clinvar ↗pm5_candidates
PS2 No de novo observation data available. No proband narratives or family studies were provided to assess de novo occurrence with confirmed paternity and maternity. Details ▾Hide ▴
Evidence considered
- V4 assertions scan returned no de novo observations.
Still missing
- No trio or family data available.
PS3 No variant-specific functional studies identified. OncoKB reports unknown oncogenic effect with no curated functional evidence. REVEL and BayesDel are in silico predictors, not functional data. No publications were found with experimental functional characterization of NM_001127208.2:c.4555G>A. Details ▾Hide ▴
Evidence considered
- OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. In silico scores (REVEL 0.272
- BayesDel -0.267) are computational predictions
- not experimental functional data.
Still missing
- No variant-specific functional assays available in literature or curated databases.
Sources
PS4 No case-control data demonstrating enrichment in affected individuals versus controls. A single COSMIC somatic occurrence (COSV113391840, n=1) does not constitute sufficient prevalence evidence for PS4 in the germline context. Details ▾Hide ▴
Evidence considered
- COSMIC reports 1 somatic observation (COSV113391840)
- no case-control or cohort prevalence data available.
Still missing
- No case-control studies or cohort prevalence data for this variant.
PM1 No evidence that residue 1519 lies within a well-established critical functional domain or mutational hotspot. Cancerhotspots.org reports no statistically significant hotspot at this position. Gene cache returned no annotated critical domains for TET2. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not significant
- exact variant not listed as hotspot. Gene cache returned empty critical_domains for TET2.
Still missing
- No annotated critical functional domain mapping for TET2 residue 1519.
PM6 No de novo observation data available. PM6 requires a de novo occurrence (without confirmation of paternity and maternity), and no such data were identified for this variant. Details ▾Hide ▴
Evidence considered
- V4 assertions scan returned no de novo observations.
Still missing
- No de novo data available.
PP1 No co-segregation data available. No family studies or pedigrees were provided to assess segregation of this variant with disease. Details ▾Hide ▴
Evidence considered
- No segregation data available in case materials or literature.
Still missing
- No family or segregation data.
PP2 No HCI prior gene-level constraint data available for TET2. The HCI prior lookup returned 'gene not supported'. Without established missense constraint metrics (Z-score or equivalent), PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
- HCI prior not available for TET2
- gene_not_supported.
Still missing
- TET2 not in HCI prior database
- no missense constraint metric available.
PP3 Multiple lines of in silico evidence do not support a deleterious effect. REVEL score 0.272 is well below the 0.5 threshold for predicted pathogenicity. BayesDel score -0.267 falls in the benign range. SpliceAI predicts no splice impact (max delta 0.00). Computational evidence is not supportive of pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL 0.272 (below 0.5 deleterious threshold). BayesDel -0.267 (negative/benign range). SpliceAI max delta 0.00 (no predicted splice impact).
Sources
PP4 No patient phenotype data available. PP4 requires a phenotype or family history highly specific for the disease, and no proband clinical information was provided. Details ▾Hide ▴
Evidence considered
- No proband narratives or phenotype data in case materials.
Still missing
- No patient phenotype available.
PP5 ClinVar classification for this variant is Uncertain significance (Variation ID 3714180) with review status 'criteria provided, single submitter' (1-star). PP5 requires a 3-star expert panel classification as pathogenic, which is not met. Details ▾Hide ▴
Evidence considered
- ClinVar VCV3714180: VUS
- single submitter (Labcorp Genetics)
- 1-star. Not 3-star expert panel pathogenic.
Sources
BA1 gnomAD maximum allele frequency is 0.050% (v2.1 Remaining individuals) or 0.051% (v4.1 Middle Eastern), far below the 1% BA1 threshold. This variant is not common enough to stand as benign. Details ▾Hide ▴
Evidence considered
- Max gnomAD subpopulation AF: 0.050% (v2.1) / 0.051% (v4.1)
- both << 1% BA1 threshold.
Sources
BS1 gnomAD maximum allele frequency is 0.050%, below the 0.3% BS1 threshold for non-VCEP adjudication. The variant is absent or too rare to meet BS1. Details ▾Hide ▴
Evidence considered
- Max gnomAD subpopulation AF: 0.050% (v2.1) / 0.051% (v4.1)
- both << 0.3% BS1 threshold.
Sources
BS2 No homozygotes observed in gnomAD (v2.1: 0 hom; v4.1: 0 hom). BS2 requires observation in the homozygous state in healthy controls, which is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0 homozygotes out of 144
- 414 alleles. v4.1: 0 homozygotes out of 1
- 537
- 566 alleles.
Sources
BS3 No well-established functional studies demonstrate no deleterious effect for this variant. In silico predictions (REVEL 0.272, BayesDel -0.267) do not constitute well-established functional evidence required for BS3. No variant-specific experimental assays were identified in the literature. Details ▾Hide ▴
Evidence considered
- In silico scores alone do not meet BS3 threshold. No variant-specific functional assays in literature or OncoKB.
Still missing
- No variant-specific functional studies demonstrating no deleterious effect.
Sources
BS4 No segregation data available. BS4 requires lack of segregation with disease in affected family members, and no family studies were provided. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No family or segregation data.
BP1 While TET2 has a loss-of-function disease mechanism, the disease spectrum includes both truncating and missense variants. The literature describes heterozygous germline TET2 missense and LOF variants in patients with ALPS-like phenotype and hematologic malignancy (PMID: 36066697, 40031954). Insufficient evidence that only truncating variants cause disease. Details ▾Hide ▴
Evidence considered
- TET2 germline disease involves both missense and LOF variants. BP1 requires that primarily truncating variants cause disease
- which is not established for TET2.
Still missing
- Disease spectrum includes missense variants
- BP1 criterion not met.
Sources
pvs1_gene_context
BP2 No evidence of this variant observed in trans with a known pathogenic variant. No phase data or variant combinations were reported. Details ▾Hide ▴
Evidence considered
- No trans-phase observations with pathogenic variants reported.
Still missing
- No phase data available.
BP5 No alternative molecular basis for disease was identified in this case. BP5 requires observation of a pathogenic variant in a different gene that explains the phenotype, and no such data were provided. Details ▾Hide ▴
Evidence considered
- No alternative molecular basis identified in case materials.
Still missing
- No data on variants in other genes.
BP6 ClinVar classification for this variant is Uncertain significance (VUS), not benign. Review status is single submitter (1-star). BP6 requires a 3-star expert panel benign classification, which is not met. Details ▾Hide ▴
Evidence considered
- ClinVar VCV3714180: VUS
- single submitter
- 1-star. Not 3-star expert panel benign.
Sources
PS5 No reputable source has recently reported this variant as pathogenic with evidence unavailable for independent evaluation. ClinVar classification is Uncertain significance by a single submitter. Details ▾Hide ▴
Evidence considered
- ClinVar VCV3714180 classified as VUS by Labcorp Genetics (single submitter
- criteria provided). No expert panel or multi-submitter pathogenic classification.
Still missing
- No external pathogenic classification report.
Sources
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (p.Gly1519Arg); does not fall into null-variant buckets (nonsense, frameshift, canonical ±1,2 splice). PVS1 generic framework not applicable to missense variants. Details ▾Hide ▴
Evidence considered
- PVS1 variant assessment confirms 'other' bucket
- variant is a missense substitution outside canonical splice sites.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/ASkipped per directive — trivially not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per directive — trivially not applicable. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo same-residue pathogenic comparator variants identified. PM5 candidate harvesting returned no candidates at position 1519; classic same-residue PM5 semantics cannot be confirmed. Details ▾Hide ▴
Evidence considered
- PM5 candidates search returned 0 same-residue candidates
- recommendation level 'not_applicable'.
Sources
pm5_candidates
BP3 N/ASkipped per directive — trivially not applicable. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis is a missense variant (c.4555G>A, p.Gly1519Arg), not a synonymous variant. BP7 applies exclusively to synonymous (silent) variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous. BP7 not applicable.
Identifiers
- Gene
- TET2
- Transcript
- NM_001127208.2
- Coding (HGVS c.)
- NM_001127208.2:c.4555G>A
- Protein (HGVS p.)
- NP_001120680.1:p.(Gly1519Arg)
- GRCh38
- chr4:105275065 G>A
- GRCh37
- chr4:106196222 G>A
- ClinVar
- 3714180
- COSMIC
- COSV113391840
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in TET2
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
64 / 1,537,566 alleles
AF 4.16e-05 · 0 homozygotes · FAF 0.000138
gnomAD v2.1
9 / 144,414 alleles
AF 6.23e-05 · 0 homozygotes · FAF 1.56e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 4.2e-05 · 64 / 1,537,566 alleles · 0 hom · FAF 0.00014
| Middle Eastern3 / 5,900 | 0.00051 |
| Ashkenazi Jewish10 / 27,322 | 0.00037 |
| Admixed American4 / 48,706 | 8.2e-05 |
| African/African American4 / 72,474 | 5.5e-05 |
| Remaining individuals3 / 59,438 | 5e-05 |
| European (non-Finnish)39 / 1,141,094 | 3.4e-05 |
| South Asian1 / 81,612 | 1.2e-05 |
0 alternate alleles recorded in 3 other groups: European (Finnish), Amish, East Asian.
gnomAD v2.1
AF 6.2e-05 · 9 / 144,414 alleles · 0 hom · FAF 1.6e-05
| Remaining individuals2 / 3,968 | 0.0005 |
| Ashkenazi Jewish3 / 6,978 | 0.00043 |
| Admixed American2 / 22,696 | 8.8e-05 |
| South Asian1 / 20,006 | 5e-05 |
| European (non-Finnish)1 / 56,098 | 1.8e-05 |
0 alternate alleles recorded in 3 other groups: African/African American, East Asian, European (Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.16242e-05; MAF= 0.00416%, 64/1537566 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000508475; MAF= 0.05085%, 3/5900 alleles, homozygotes = 0); grpmax FAF= 0.00013848.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.23208e-05; MAF= 0.00623%, 9/144414 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000504032; MAF= 0.05040%, 2/3968 alleles, homozygotes = 0); grpmax FAF= 1.557e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.272
- BayesDel
- -0.267
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product. REVEL score 0.272 is well below the 0.5 threshold for predicted deleteriousness. BayesDel score -0.267 falls in the benign range. SpliceAI predicts no splice alteration (max delta 0.00). Three independent in silico predictors consistently suggest a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.272 (<0.5
- benign). BayesDel -0.267 (negative
- benign range). SpliceAI max delta 0.00 (no predicted splice impact). Three concordant benign predictions.
Sources
PP3 Multiple lines of in silico evidence do not support a deleterious effect. REVEL score 0.272 is well below the 0.5 threshold for predicted pathogenicity. BayesDel score -0.267 falls in the benign range. SpliceAI predicts no splice impact (max delta 0.00). Computational evidence is not supportive of pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL 0.272 (below 0.5 deleterious threshold). BayesDel -0.267 (negative/benign range). SpliceAI max delta 0.00 (no predicted splice impact).
Sources
BP7 N/AThis is a missense variant (c.4555G>A, p.Gly1519Arg), not a synonymous variant. BP7 applies exclusively to synonymous (silent) variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous. BP7 not applicable.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.272. BayesDel score = -0.266636.
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
64 / 1,537,566 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/variation/3714180/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/4-106196222-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr4-105275065-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/4-105275065-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001127208.2%3Ac.4…
- OncoKB ↗www.oncokb.org/gene/TET2/G1519R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=194831498
- 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= 4.16242e-05; MAF= 0.00416%, 64/1537566 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000508475; MAF= 0.05085%, 3/5900 alleles, homozygotes = 0); grpmax FAF= 0.00013848.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.23208e-05; MAF= 0.00623%, 9/144414 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000504032; MAF= 0.05040%, 2/3968 alleles, homozygotes = 0); grpmax FAF= 1.557e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant is present in ClinVar (Variation ID: 3714180); submission details unavailable.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.272. BayesDel score = -0.266636.
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; COSV113391840, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.