NM_001127208.2:c.2926C>T

TET2 · NP_001120680.1:p.(Gln976Ter) · NM_001127208.2

GRCh37: chr4:106158025 C>T · GRCh38: chr4:105236868 C>T

Gene: TET2 Transcript: NM_001127208.2

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

TET2

Transcript

NM_001127208.2

Protein

NP_001120680.1:p.(Gln976Ter)

gnomAD AF

2.4781489218813115e-06 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The TET2 c.2926C>T (p.Gln976Ter; p.Q976*) variant has been reported in curated somatic cancer resources and has not been reported in ClinVar.

This variant is present at very low frequency in population databases, with allele frequency 7.96388e-06 in gnomAD v2.1 and 2.47815e-06 in gnomAD v4.1, both below the PM2 threshold.

Available gene-level studies support TET2 loss-of-function biology and structural importance of the C-terminal catalytic region, but no variant-specific functional assay for p.(Gln976Ter) was identified.

Computational review showed no significant predicted splice effect by SpliceAI, with a maximum delta score of 0.01; REVEL was unavailable, and BayesDel score 0.294732 did not provide sufficient support for PP3 or BP4 for this nonsense variant.

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 nonsense change, p.(Gln976Ter), in TET2. Available gene-level evidence supports loss of function as a germline disease mechanism for TET2, and the generic PVS1 framework is eligible. The premature stop occurs well upstream of the terminal exon structure for this transcript, supporting a loss-of-function effect rather than a tolerated distal truncation.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified for a different nucleotide change producing the same amino acid consequence with an established pathogenic classification, so PS1 could not be assessed.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with parental confirmation was identified for this variant, so PS2 was not met.	clinvar
PS3	Not assessed	Published TET2 studies describe gene-level functional and structural effects relevant to loss of function, but no variant-specific well-established functional assay result for p.(Gln976Ter) was identified. Available evidence therefore does not support applying PS3.	PMID:21057493 PMID:24315485 oncokb
PS4	Not assessed	This variant has not been reported in ClinVar, and no affected-case enrichment data for germline disease were identified. Somatic observations alone do not establish PS4 for germline interpretation.	clinvar oncokb
PM1	N/A	PM1 is not applied here because this is a truncating variant rather than a missense change at a defined critical residue, and the residue is not shown to lie in a statistically significant hotspot.	hotspots PMID:24315485
PM2	Met	This variant is present at very low frequency in population databases. The gnomAD v2.1 allele frequency is 7.96388e-06 (2/251134 alleles), and the gnomAD v4.1 allele frequency is 2.47815e-06 (4/1614108 alleles), both below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	No data were identified showing this variant in trans with another pathogenic variant in a recessive disease context, so PM3 could not be assessed.
PM4	N/A	PM4 is not applicable because this variant is a nonsense substitution, not a protein length change caused by an in-frame indel or stop-loss variant.
PM5	N/A	PM5 was not applied because classic same-residue PM5 semantics could not be confirmed for this framework, and no same-residue pathogenic comparator variants were established.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified for this variant, so PM6 was not met.	clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 could not be applied.	clinvar
PP2	N/A	PP2 is not applicable because this variant is not a missense change.
PP3	Not met	SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01. REVEL was unavailable, and BayesDel score 0.294732 does not provide a validated basis to apply PP3 for this nonsense variant. Available computational evidence therefore does not support PP3.	spliceai bayesdel
PP4	Not assessed	No phenotype-specific clinical data were provided that would establish a highly specific TET2-related presentation for this individual, so PP4 could not be assessed.
PP5	Not assessed	This variant is absent from ClinVar, and no germline reputable-source pathogenic assertion suitable for PP5 was identified.	clinvar
BA1	Not met	Population frequency does not meet BA1. The highest observed gnomAD v4.1 allele frequency is 2.47815e-06 overall, which is far below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	Population frequency does not meet BS1. The highest observed population frequency is 4.62022e-05 in gnomAD v2.1 Finnish samples, which is below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals at a level sufficient to apply BS2.
BS3	Not assessed	Available studies provide gene-level functional and structural context for TET2, but no well-established variant-specific assay showing normal function for p.(Gln976Ter) was identified. BS3 was therefore not applied.	PMID:21057493 PMID:24315485 oncokb
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 could not be assessed.	clinvar
BP1	N/A	BP1 is not applicable because this variant is not a missense change, and available TET2 evidence supports loss of function rather than a predominantly benign truncating mechanism.	pvs1_gene_context
BP2	Not assessed	No phase data were identified showing this variant in cis with a pathogenic variant or in trans with a pathogenic variant in a dominant condition, so BP2 could not be assessed.
BP3	N/A	BP3 is not applicable because this variant is not an in-frame deletion or insertion in a repetitive region.
BP4	Not met	Computational evidence does not support a benign interpretation. Although SpliceAI shows no significant splice effect with a maximum delta score of 0.01, this is a nonsense variant and there is no broader computational evidence sufficient to support BP4.	spliceai bayesdel
BP5	Not assessed	No alternate molecular cause explaining the phenotype was identified, so BP5 could not be assessed.
BP6	Not assessed	This variant is absent from ClinVar, and no germline reputable-source benign assertion suitable for BP6 was identified.	clinvar
BP7	N/A	BP7 is not applicable because this variant is a nonsense coding change, not a synonymous or deep intronic variant.

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