NM_001127208.2:c.3796A>T

TET2 · NP_001120680.1:p.(Asn1266Tyr) · NM_001127208.2

GRCh37: chr4:106164928 A>T · GRCh38: chr4:105243771 A>T

Gene: TET2 Transcript: NM_001127208.2

Final call

VUS

PM2 supporting

Variant details

Gene

TET2

Transcript

NM_001127208.2

Protein

NP_001120680.1:p.(Asn1266Tyr)

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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	Missense 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.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No known pathogenic variant with the same amino acid change (p.Asn1266Tyr) has been reported in ClinVar or the literature.	clinvar pm5_candidates
PS2	Not assessed	No de novo data with confirmed parentage are available for this variant.
PS3	Not met	No variant-specific functional studies were identified. OncoKB classifies this alteration as 'Unknown Oncogenic Effect' with no reviewed functional evidence.	oncokb
PS4	Not met	No case-control studies comparing variant prevalence in affected versus unaffected individuals are available.
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion; no gene-specific VCEP framework exists for TET2 to define a PS5 rule.
PM1	Not met	Residue 1266 is not located within a statistically significant mutational hotspot or a well-established critical functional domain without benign variation.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	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.	pm5_candidates clinvar
PM6	Not assessed	No de novo data are available for this variant.
PP1	Not assessed	No co-segregation data are available for this variant.
PP2	Not assessed	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.
PP3	Not met	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).	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or clinical information is available to evaluate whether the presentation is highly specific for TET2-related germline disease.
PP5	Not met	This variant is absent from ClinVar. No reputable source has reported NM_001127208.2:c.3796A>T as pathogenic.	clinvar
BA1	Not met	Variant is absent from gnomAD population databases (AF=0% across all populations). Does not meet the BA1 threshold of >5% allele frequency.	gnomad_v2 gnomad_v4
BS1	Not met	Variant is absent from gnomAD population databases (AF=0%). Does not meet the BS1 threshold of >0.3% allele frequency.	gnomad_v2 gnomad_v4
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional studies demonstrating no deleterious effect are available for this variant.
BS4	Not assessed	No segregation data are available to evaluate lack of co-segregation with disease.
BP1	Not met	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.
BP2	Not assessed	No phase data are available for this variant (no observations in trans with a pathogenic variant or in cis with a pathogenic variant).
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not assessed	No data are available on an alternate molecular basis for disease in a case carrying this variant.
BP6	Not met	This variant is absent from ClinVar. No reputable source has reported NM_001127208.2:c.3796A>T as benign.	clinvar
BP7	N/A	Variant is a missense substitution (c.3796A>T, p.Asn1266Tyr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	In-frame indel criterion; this variant is a single-nucleotide substitution, not an in-frame insertion or deletion.
PM3	N/A	Recessive disorder criterion; TET2 germline disease follows an autosomal dominant pattern (heterozygous LoF variants cause disease).
PM4	N/A	Non-recurrent event criterion (indels, CNVs); this variant is a single-nucleotide substitution.

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