TET2 c.877_901dupAGTGAGGCCTGTGATGCTGATGATG, p.Ala301GlufsTer2

NM_001127208.2:c.877_901dupAGTGAGGCCTGTGATGCTGATGATG

Classification Summary

Likely Pathogenic

Final classification of NM_001127208.2:c.877_901dupAGTGAGGCCTGTGATGCTGATGATG in gene TET2 is Likely Pathogenic. This classification is supported by the application of PVS1 due to the truncating nature of the variant and PM2 due to its absence in population databases, indicating it is not a common variant.

Population Frequency

0.0 in 100,000

Rare

ClinVar Classification

Uncertain Significance (VUS)

0 publications

REVEL Score

N/A

Not Available

COSMIC Recurrence

0 occurrences

No Criteria Applied

Classification Evidence

Very Strong (PVS)

PVS1

Strong (PS/BS)

None applied

Moderate (PM/BA)

PM2

Supporting (PP/BP)

None applied

ClinVar COSMIC OncoKB JAX-CKB SpliceAI

Created: 2025-04-07T09:37:51.887257

Detailed Information

Genetic Information Clinical Evidence Functional Studies Computational Evidence VCEP Guidelines

Genetic Information

Gene & Transcript Details

Gene

TET2

Transcript

                                        
                                            NM_001127208.3
                                        
                                                    MANE Select

Total Exons

Strand

Forward (+)

Reference Sequence

                                        NC_000004.11
                                    

Alternative Transcripts

ID	Status	Details
NM_001127208.1	Alternative	11 exons \| Forward
NM_001127208.2	RefSeq Select	11 exons \| Forward

Variant Details

HGVS Notation

NM_001127208.2:c.877_901dupAGTGAGGCCTGTGATGCTGATGATG

Protein Change

A301Efs*2

Location

Exon 3 (Exon 3 of 11)

5' Exon Structure (11 total) 3'

Functional Consequence

Loss of Function

Related Variants

No evidence of other pathogenic variants at position 301 in gene TET2

Variant interpretation based on transcript NM_001127208.3

Clinical Evidence

Population Frequency

Global Frequency

0.0 in 100,000

Extremely Rare

Global: 0.0%

0.0005%

0.001%

0.01%

0.05%

1%+

ACMG Criteria Applied

PM2

This variant is rare in the population (0.000000% MAF).

ClinVar 2025-04-07T09:36:57.099480

Classification

Uncertain Significance (VUS)

Based on 0 submitter reviews in ClinVar

Submitter Breakdown

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Publications

0 publications

Clinical Statement

This variant has been reported in ClinVar as Uncertain Significance (1 clinical laboratories).

COSMIC

COSMIC ID

Unknown

Recurrence

0 occurrences

PM1 Criteria

Not Applied

Accessing full COSMIC database details requires institutional login or subscription. External links may prompt for authentication.

Functional Domain

Cancer Hotspots

Hotspot Status

Not a hotspot

Domain Summary

This variant is not located in a mutational hotspot or critical domain (0 mutations).

Related Variants in This Domain

No evidence of other pathogenic variants at position 301 in gene TET2

Functional Studies

Functional Impact

OncoKB JAX-CKB

Summary

The variant TET2 A301Efs*2 has not been functionally characterized in the provided sources.

Computational Evidence

Pathogenicity Predictions

Predictor Consensus

Unknown

PP3 Applied

SpliceAI Scores Window: ±500bp

Effect Type	Score	Position
- Acceptor Loss	0.0	-112 bp
- Donor Loss	0.05	-1 bp
+ Acceptor Gain	0.02	78 bp
+ Donor Gain	0.0	-424 bp

High impact (≥0.5)

Medium impact (0.2-0.49)

Low impact (<0.2)

VCEP Guidelines

Applied ACMG/AMP Criteria

PVS1

PVS1 (Very Strong)

According to VCEP guidelines: 'PVS1 – Null variant in a gene where loss of function (LoF) is a known mechanism of disease.' The evidence for this variant shows: it is a truncating variant (A301Efs*2) in TET2, a gene where loss of function is associated with disease. Therefore, this criterion meets the requirements because the variant is a null variant in a gene known to be affected by loss of function.

PM2

PM2 (Moderate)

According to VCEP guidelines: 'PM2 – Absent from controls (or at extremely low frequency if recessive).' The evidence for this variant shows: it is not found in population databases such as gnomAD, indicating it is absent from controls. Therefore, this criterion meets the requirements because the variant is not present in the general population.