NM_001127208.2:c.4164_4167delGCAG

TET2 · NP_001120680.1:p.(Met1388IlefsTer59) · NM_001127208.2

GRCh37: chr4:106190885 TGCAG>T · GRCh38: chr4:105269728 TGCAG>T

Gene: TET2 Transcript: NM_001127208.2

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

TET2

Transcript

NM_001127208.2

Protein

NP_001120680.1:p.(Met1388IlefsTer59)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The TET2 c.4164_4167del (p.Met1388IlefsTer59; p.M1388Ifs*59) variant has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing it below the 0.1% rarity threshold used for PM2 in non-VCEP review.

Published TET2 studies identified through curated review show that leukemia-associated TET2 alterations impair 5-hydroxymethylcytosine generation, and structural work supports the functional importance of the C-terminal catalytic region, which is consistent with loss of function as a disease-relevant mechanism for truncating variants.

SpliceAI predicts no significant additional splice effect for this deletion, with a maximum delta score of 0.00; REVEL and BayesDel are not available for this variant type.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	This variant is a frameshift deletion predicted to cause p.(Met1388IlefsTer59) and truncate the protein well before the normal C-terminus. Germline loss of function is supported as a disease-relevant mechanism for TET2, and the generic ClinGen SVI PVS1 framework supports applying PVS1 for this type of truncating variant.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 applies to a different nucleotide change producing the same amino acid substitution. This variant is a frameshift deletion, so PS1 is not applicable.
PS2	Not assessed	No confirmed de novo data were identified for this variant, so PS2 cannot be assessed.
PS3	Not assessed	Published TET2 functional studies were identified, but the retrieved evidence does not show a direct functional assay of this exact deletion. Available evidence therefore does not support applying PS3 at this stage.	oncokb PMID:21057493 PMID:24315485
PS4	Not assessed	No exact-variant case enrichment or case-control data were identified for this variant, so PS4 cannot be applied.	clinvar
PM1	Not assessed	Available evidence does not establish that this variant lies in a confirmed mutational hotspot or a sufficiently defined critical region without benign variation, so PM1 is not assessed.	hotspots PMID:24315485
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the non-VCEP PM2 threshold of 0.1% population frequency and supports rarity in reference populations.	gnomad_v2 gnomad_v4
PM3	Not assessed	No data were identified showing this variant in trans with another pathogenic variant, so PM3 cannot be assessed.
PM4	N/A	PM4 is generally used for protein length changes from in-frame indels or stop-loss variants. This variant is a frameshift truncating variant already captured by PVS1, so PM4 is not applied separately.	pvs1_variant_assessment
PM5	N/A	PM5 applies to a novel missense change at an amino acid residue where a different pathogenic missense change is established. This variant is a frameshift deletion, so PM5 is not applicable.
PM6	Not assessed	No assumed de novo report was identified for this variant, so PM6 cannot be assessed.
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be assessed.
PP2	N/A	PP2 is a missense-based criterion and is not applicable to this frameshift deletion.
PP3	N/A	PP3 is not applied here because this variant is a frameshift deletion rather than a missense or splice-consensus change requiring computational pathogenicity support. SpliceAI showed no significant additional splice effect (max delta score 0.00), and REVEL and BayesDel are not available for this deletion.	spliceai
PP4	Not assessed	No phenotype information specific enough for PP4 was identified, so this criterion cannot be assessed.
PP5	Not assessed	No qualifying reputable-source pathogenic classification was identified for this exact variant, so PP5 is not assessed.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is below the 1% BA1 threshold and BA1 is not met.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is below the 0.3% BS1 threshold and BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals in a manner suitable for BS2, so the criterion is not assessed.
BS3	Not assessed	Available evidence does not show well-established functional studies demonstrating a normal effect for this exact deletion, so BS3 cannot be applied.	oncokb PMID:21057493 PMID:24315485
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 cannot be assessed.
BP1	N/A	BP1 is a missense-based criterion and is not applicable to this frameshift deletion.
BP2	Not assessed	No data were identified showing this variant in cis with a pathogenic variant or in trans in a manner supporting BP2, so the criterion is not assessed.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions without known function. This variant is a frameshift deletion, so BP3 is not applicable.
BP4	N/A	BP4 is not applied here because this variant is a frameshift deletion rather than a variant type for which benign computational protein prediction is informative. SpliceAI predicts no significant additional splice effect (max delta score 0.00), but that does not outweigh the truncating consequence.	spliceai
BP5	Not assessed	No alternate molecular explanation for a specific phenotype was identified, so BP5 cannot be assessed.
BP6	Not assessed	No qualifying reputable-source benign classification was identified for this exact variant, so BP6 is not assessed.	clinvar
BP7	N/A	BP7 applies to synonymous or certain intronic variants with no predicted splice impact. This variant is a coding frameshift deletion, so BP7 is not applicable.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.