TET2c.3796A>TUncertain significance

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Variant interpretation report

TET2 c.3796A>T, p.(Asn1266Tyr)

NM_001127208.2:c.3796A>T NP_001120680.1:p.(Asn1266Tyr) View identifiers

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.

About TET2

No gene-level summary was recorded for this case.

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: 0

Pathogenic criteria applied · 1

PM2Supporting

PM2 · supporting

This variant is absent from gnomAD population databases (v2.1 exomes and v4.1 genomes, combined 0/1,551,256 alleles; also absent from gnomAD-Canada v1.0), meeting the PM2 threshold of <0.1% allele frequency.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

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; combination = 1 supporting, 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

0 / 1,551,256 alleles

gnomAD v4.1: 0 / 1,551,256 alleles. Recorded AF 0. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. 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 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

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

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 1 met · 13 not met · 9 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_001127208.2:c.3796A>T (p.Asn1266Tyr) is a missense variant in exon 6 of TET2. It is absent from gnomAD population databases (0/1,551,256 alleles) and from ClinVar.

The variant meets PM2 at supporting strength due to complete absence from large population cohorts.

In silico predictions are conflicting: REVEL score of 0.707 is indeterminate; BayesDel score of 0.152 does not support pathogenicity; SpliceAI predicts no splicing impact (max delta=0.01). PP3 and BP4 are not met.

No variant-specific functional studies, de novo reports, segregation data, case-control comparisons, or ClinVar classifications are available for this variant. PS3, PS2/PM6, PP1, PS4, and PP5 are all not met or not assessed.

Under ACMG/AMP 2015 generic rules, one supporting pathogenic criterion (PM2) with no benign criteria yields a classification of Uncertain Significance.

Met · 1

PM2 SupportingThis variant is absent from gnomAD population databases (v2.1 exomes and v4.1 genomes, combined 0/1,551,256 alleles; also absent from gnomAD-Canada v1.0), meeting the PM2 threshold of <0.1% allele frequency. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: absent
gnomAD v4.1: 0/1
551
256 alleles (AF=0.000%)
0 homozygotes
gnomAD-Canada v1.0: absent

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 13 · evaluated, threshold not reached

PS1 No known pathogenic variant with the same amino acid change (p.Asn1266Tyr) has been reported in ClinVar or the literature. Details ▾Hide ▴

Evidence considered

This variant is absent from ClinVar
no submissions found for TET2 c.3796A>T or p.Asn1266Tyr
PM5 candidate search confirmed no pathogenic comparator at residue 1266

Sources

clinvar ↗pm5_candidates

PS3 No variant-specific functional studies were identified. OncoKB classifies this alteration as 'Unknown Oncogenic Effect' with no reviewed functional evidence. Details ▾Hide ▴

Evidence considered

OncoKB: Unknown Oncogenic Effect
no variant-specific functional evidence curated
No publications with functional characterization of p.Asn1266Tyr identified

Still missing

No functional assays performed for this variant

Sources

oncokb ↗

PS4 No case-control studies comparing variant prevalence in affected versus unaffected individuals are available. Details ▾Hide ▴

Evidence considered

Variant is absent from gnomAD (0/1
551
256 alleles) but no affected cohort data exist for comparison

Still missing

No case-control or cohort enrichment data available

PM1 Residue 1266 is not located within a statistically significant mutational hotspot or a well-established critical functional domain without benign variation. Details ▾Hide ▴

Evidence considered

Cancer Hotspots: residue not significant
exact variant not listed
No domain-level constraint data available for TET2 residue 1266

Still missing

No functional domain annotation for residue 1266

PM5 No known pathogenic missense variant at amino acid residue 1266 has been identified in ClinVar. Zero same-residue comparator candidates were found during automated PM5 harvesting. Details ▾Hide ▴

Evidence considered

PM5 candidate search: 0 same-residue candidates
eligible_for_classic_pm5_search=false
ClinVar: no entries for any variant at TET2 residue 1266

Sources

pm5_candidatesclinvar ↗

PP3 Computational evidence is conflicting and does not meet the threshold for multiple lines of support. REVEL score of 0.707 is in the indeterminate range (below the commonly used pathogenic threshold of 0.75). BayesDel score of 0.152 does not support a deleterious interpretation. SpliceAI predicts no splicing impact (max delta=0.01). Details ▾Hide ▴

Evidence considered

REVEL: 0.707 (indeterminate
below pathogenic threshold of 0.75)
BayesDel (noAF): 0.152 (indeterminate
leaning benign)
SpliceAI: max delta 0.01 (no predicted splice impact)
HCI prior: not available for TET2

Sources

revelbayesdelspliceai ↗

PP5 This variant is absent from ClinVar. No reputable source has reported NM_001127208.2:c.3796A>T as pathogenic. Details ▾Hide ▴

Evidence considered

ClinVar: 0 submissions
absent from all ClinVar records

Sources

clinvar ↗

BA1 Variant is absent from gnomAD population databases (AF=0% across all populations). Does not meet the BA1 threshold of >5% allele frequency. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: absent
gnomAD v4.1: 0/1
551
256 alleles (AF=0.000%)

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 Variant is absent from gnomAD population databases (AF=0%). Does not meet the BS1 threshold of >0.3% allele frequency. Details ▾Hide ▴

Evidence considered

gnomAD v4.1: 0/1
551
256 alleles (AF=0.000%)
highest subpopulation AF=0.000%

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 No observations of this variant in a homozygous state or in trans with a known pathogenic TET2 variant. The criterion requires actual observations, not absence. Details ▾Hide ▴

Evidence considered

gnomAD v4.1: 0 homozygotes
variant is completely absent from the database

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP1 TET2 germline disease is not established to be caused exclusively by truncating variants. Published literature (PMID:36066697, PMID:40031954) describes both loss-of-function and heterozygous missense variants associated with ALPS-like phenotype and hematologic malignancy. Missense variants in functional domains may also be pathogenic. Details ▾Hide ▴

Evidence considered

PMID:36066697: reports germline TET2 mutations including missense in ALPS-like phenotype
PMID:40031954: describes heterozygous germline TET2 loss-of-function variants
but also establishes that missense variants in key domains may be pathogenic

BP4 Computational evidence is conflicting and does not support a consensus benign prediction. REVEL score of 0.707 suggests possible functional impact, which is inconsistent with the benign interpretation required by BP4. BayesDel 0.152 is indeterminate. Details ▾Hide ▴

Evidence considered

REVEL: 0.707 (above 0.5
suggesting possible functional impact)
BayesDel: 0.152 (indeterminate)
SpliceAI: max delta 0.01 (no splice impact
but insufficient alone for BP4)

Sources

revelbayesdelspliceai ↗

BP6 This variant is absent from ClinVar. No reputable source has reported NM_001127208.2:c.3796A>T as benign. Details ▾Hide ▴

Evidence considered

ClinVar: 0 submissions
absent from all ClinVar records

Sources

clinvar ↗

Not assessed · 9 · no assessment recorded

PS2 No de novo data with confirmed parentage are available for this variant. Details ▾Hide ▴

Evidence considered

No publications or databases report de novo occurrence of NM_001127208.2:c.3796A>T

Still missing

No de novo testing data available

PM6 No de novo data are available for this variant. Details ▾Hide ▴

Evidence considered

No publications or databases report de novo occurrence of NM_001127208.2:c.3796A>T

Still missing

No de novo testing data available

PP1 No co-segregation data are available for this variant. Details ▾Hide ▴

Evidence considered

No family studies or pedigree data available for NM_001127208.2:c.3796A>T

Still missing

No co-segregation or family data available

PP2 Insufficient gene-level constraint data to determine whether TET2 has a low rate of benign missense variation. HCI prior scores are not available for TET2, and TET2 germline disease involves both loss-of-function and missense mechanisms. PP2 cannot be reliably applied without constraint metrics. Details ▾Hide ▴

Evidence considered

HCI prior: not supported for TET2 (gene_not_supported)
TET2 germline disease mechanism includes both LoF and missense variants per published literature

Still missing

No gene-level missense constraint scores available (HCI prior unavailable)

PP4 No patient phenotype or clinical information is available to evaluate whether the presentation is highly specific for TET2-related germline disease. Details ▾Hide ▴

Evidence considered

No patient phenotype data provided in case materials

Still missing

No patient phenotype or clinical history provided

BS3 No well-established functional studies demonstrating no deleterious effect are available for this variant. Details ▾Hide ▴

Evidence considered

No functional assays characterizing p.Asn1266Tyr identified in the literature

Still missing

No functional data available for this variant

BS4 No segregation data are available to evaluate lack of co-segregation with disease. Details ▾Hide ▴

Evidence considered

No family studies or pedigree data available for NM_001127208.2:c.3796A>T

Still missing

No segregation data available

BP2 No phase data are available for this variant (no observations in trans with a pathogenic variant or in cis with a pathogenic variant). Details ▾Hide ▴

Evidence considered

Variant is completely absent from population and clinical databases
no phase information available

Still missing

No phase data available

BP5 No data are available on an alternate molecular basis for disease in a case carrying this variant. Details ▾Hide ▴

Evidence considered

No clinical case data with alternate molecular diagnosis available

Still missing

No case data with alternate molecular diagnosis

Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AMissense variant (p.Asn1266Tyr) does not fall into the null-variant buckets defined by the ClinGen SVI PVS1 framework (PMC6185798); PVS1 is restricted to nonsense, frameshift, and canonical ±1,2 splice consensus variants. Details ▾Hide ▴

Evidence considered

NM_001127208.2:c.3796A>T is a missense substitution (Asn→Tyr at position 1266)
Variant bucket classified as 'other' by pvs1_variant_assessment
apply_generic_pvs1_framework=false
TET2 LoF mechanism is supported for germline disease but PVS1 requires a null variant class

Sources

pvs1_variant_assessmentpvs1_generic_framework ↗

PM3 N/ARecessive disorder criterion; TET2 germline disease follows an autosomal dominant pattern (heterozygous LoF variants cause disease). Details ▾Hide ▴

No further detail was recorded.

PM4 N/ANon-recurrent event criterion (indels, CNVs); this variant is a single-nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

BP3 N/AIn-frame indel criterion; this variant is a single-nucleotide substitution, not an in-frame insertion or deletion. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AVariant is a missense substitution (c.3796A>T, p.Asn1266Tyr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴

Evidence considered

NM_001127208.2:c.3796A>T encodes p.Asn1266Tyr (missense)

PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion; no gene-specific VCEP framework exists for TET2 to define a PS5 rule. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: TET2
Transcript: NM_001127208.2
Coding (HGVS c.): NM_001127208.2:c.3796A>T
Protein (HGVS p.): NP_001120680.1:p.(Asn1266Tyr)
GRCh38: chr4:105243771 A>T
GRCh37: chr4:106164928 A>T

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 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 0 / 1,551,256 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 / 1,551,256 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%, 0/1551256 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/72994 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -92 bp

0.010

SpliceAI acceptor gainat -223 bp

0.000

SpliceAI donor lossat +7 bp

0.000

SpliceAI donor gainat -2 bp

0.010

Pangolin splice lossmagnitude shown

-0.000

Pangolin splice gain

0.010

Other predictors

REVEL: 0.707
BayesDel: 0.152

How the predictions were used

Evidence considered

REVEL: 0.707 (indeterminate
below pathogenic threshold of 0.75)
BayesDel (noAF): 0.152 (indeterminate
leaning benign)
SpliceAI: max delta 0.01 (no predicted splice impact)
HCI prior: not available for TET2

Sources

revelbayesdelspliceai ↗

Evidence considered

REVEL: 0.707 (above 0.5
suggesting possible functional impact)
BayesDel: 0.152 (indeterminate)
SpliceAI: max delta 0.01 (no splice impact
but insufficient alone for BP4)

Sources

revelbayesdelspliceai ↗

BP7 N/AVariant is a missense substitution (c.3796A>T, p.Asn1266Tyr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴

Evidence considered

NM_001127208.2:c.3796A>T encodes p.Asn1266Tyr (missense)

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.707. BayesDel score = 0.152069.

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 0 / 1,551,256 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.010 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

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

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 = 0.01). REVEL score = 0.707. BayesDel score = 0.152069.

Functional

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.