Variant classification summary

NM_001127208.2:c.3784C>T

TET2 · NP_001120680.1:p.(Arg1262Trp) · NM_001127208.2

GRCh37: chr4:106164916 C>T · GRCh38: chr4:105243759 C>T

Gene: TET2 Transcript: NM_001127208.2

Final call

VUS

PM2 moderate

Variant details

Gene

TET2

Transcript

NM_001127208.2

Protein

NP_001120680.1:p.(Arg1262Trp)

gnomAD AF

4.512263041729409e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TET2 c.3784C>T (p.Arg1262Trp; p.R1262W) variant has not been reported in ClinVar.

2

This variant is present at low frequency in gnomAD v2.1 and v4.1, with the highest observed frequency 0.00648% (1/15,424 alleles) in European non-Finnish individuals in gnomAD v2.1, which is below the 0.1% PM2 threshold and below the BS1 (>0.3%) and BA1 (>1%) thresholds.

3

No variant-specific functional study establishing either a damaging effect or normal function was identified; the available published TET2 structural study provides protein-domain context but does not assay p.Arg1262Trp directly.

4

Computational evidence is mixed overall: SpliceAI predicts no significant splice impact (max delta score 0.02), while REVEL is 0.536 and BayesDel is 0.118577, which does not provide concordant support for either PP3 or BP4.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	N/A	This variant is a missense substitution, p.Arg1262Trp (p.R1262W), and available splice prediction does not support a loss-of-function splicing effect. Generic PVS1 was reviewed because germline loss of function is an established disease mechanism for TET2, but this specific variant does not fall into the nonsense, frameshift, or canonical splice categories used for default PVS1 application.	pvs1_gene_context pvs1_variant_assessment spliceai pvs1_generic_framework
PS1	Not met	No pathogenic or likely pathogenic variant producing the same amino acid change was identified. ClinVar did not contain this variant, and no same-amino-acid comparator supporting PS1 was retrieved.	clinvar pm5_candidates
PS2	Not met	No confirmed de novo occurrence with established maternity and paternity was identified for this variant.	clinvar
PS3	Not met	No well-established functional study showing a damaging effect of p.Arg1262Trp was identified. The retrieved TET2 publication provides structural context for the protein but does not test this variant directly.	oncokb PMID:24315485
PS4	Not met	No case-control enrichment data or other evidence showing this variant is significantly more common in affected individuals than in controls was identified.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	Available evidence does not establish that Arg1262 lies in a mutational hotspot or a well-defined critical region without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this residue, and structural domain context alone is not sufficient for PM1.	hotspots PMID:24315485
PM2	Met	This variant is rare in population databases. In gnomAD v2.1 it was seen at 0.00319% overall (1/31,394 alleles) with a highest subpopulation frequency of 0.00648% (1/15,424 alleles), and in gnomAD v4.1 it was seen at 0.00045% overall (7/1,551,328 alleles) with a highest subpopulation frequency of 0.00244% (1/40,926 alleles); these values are below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4
PM3	N/A	No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disease context, so PM3 is not applicable from the available data.
PM4	N/A	This variant is a missense substitution and does not cause a protein length change from an in-frame insertion, deletion, or stop-loss event.
PM5	N/A	PM5 was not applied because classic same-residue PM5 semantics could not be confirmed safely for this gene/framework, and no qualifying same-residue pathogenic comparator was retrieved.	pm5_candidates
PM6	Not met	No presumed de novo occurrence of this variant was identified.	clinvar
PP1	Not met	No segregation data were identified showing that this variant cosegregates with disease in a family.	clinvar
PP2	Not assessed	Available evidence does not establish that TET2 is a gene in which missense variation is a common disease mechanism and benign missense variation is unusually low, so PP2 was not assessed.
PP3	Not met	Computational evidence is mixed and does not provide concordant support for a deleterious effect. SpliceAI predicts no significant splice impact with a max delta score of 0.02, while REVEL is 0.536 and BayesDel is 0.118577, which is not sufficient as a consistent multi-tool pathogenic signal.	spliceai revel bayesdel
PP4	Not assessed	No phenotype information was provided that would allow assessment of whether the clinical presentation is highly specific for a TET2-related disorder.
PP5	N/A	No pathogenic assertion from a reputable external source without available primary evidence was identified for this variant.	clinvar
BA1	Not met	Population frequency does not meet the stand-alone benign threshold. The highest observed frequency was 0.00648% in gnomAD v2.1, which is far below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Population frequency does not exceed the benign strong threshold. The highest observed frequency was 0.00648% in gnomAD v2.1, which is below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	The available population data show only rare allele observations and no homozygotes, which does not support observation in healthy adults at a level expected for BS2.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional study showing normal or near-normal function of p.Arg1262Trp was identified.	oncokb PMID:24315485
BS4	Not met	No data were identified showing lack of segregation of this variant with disease.	clinvar
BP1	Not assessed	Although germline loss of function is supported as a disease mechanism in TET2, the available evidence does not establish that missense variation is an uncommon pathogenic mechanism in this gene, so BP1 was not assessed.	pvs1_gene_context
BP2	Not assessed	No phase information or co-occurrence data were identified to assess BP2.
BP3	N/A	This is not an in-frame insertion or deletion in a repetitive region without known function, so BP3 is not applicable.
BP4	Not met	Computational evidence does not provide concordant benign support. SpliceAI predicts no significant splice impact with a max delta score of 0.02, but REVEL is 0.536 and BayesDel is 0.118577, so the overall in silico profile is not consistently benign.	spliceai revel bayesdel
BP5	Not assessed	No phenotype data or alternate molecular diagnosis information were available to assess whether another cause fully explains the clinical presentation.
BP6	N/A	No benign assertion from a reputable external source without available primary evidence was identified for this variant.	clinvar
BP7	N/A	This variant is missense rather than synonymous or deep intronic, so BP7 is not applicable.	spliceai

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