NM_001127208.2:c.4139A>C

TET2 · NP_001120680.1:p.(His1380Pro) · NM_001127208.2

GRCh37: chr4:106190861 A>C · GRCh38: chr4:105269704 A>C

Gene: TET2 Transcript: NM_001127208.2

Final call

Likely Benign

PM2 supporting BP1 supporting benign BP4 supporting benign

Variant details

Gene

TET2

Transcript

NM_001127208.2

Protein

NP_001120680.1:p.(His1380Pro)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

Variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases, meeting PM2 at supporting strength.

TET2 loss-of-function variants are an established germline disease mechanism; this missense variant (p.His1380Pro) occurs in a gene where truncating variants are the primary known cause of disease, meeting BP1 at supporting strength.

Multiple computational tools predict no significant impact: BayesDel score 0.120 (benign) and SpliceAI max delta 0.00 (no splicing alteration), meeting BP4 at supporting strength.

REVEL score of 0.657 is intermediate and does not qualify for PP3; no other pathogenic criteria are met. Overall classification: Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules (PM2_supporting + BP1_supporting + BP4_supporting).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice consensus). This variant is a missense substitution (c.4139A>C, p.His1380Pro) and does not fall into any PVS1 null-variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No prior report of a pathogenic variant resulting in the same amino acid change (p.His1380Pro) was identified. The variant is absent from ClinVar and no literature reports this specific amino acid substitution as pathogenic.	clinvar
PS2	Not assessed	No de novo data available for this variant.
PS3	Not assessed	No variant-specific functional studies identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' and provides no reviewed functional evidence. COSMIC reports somatic occurrence (COSV54423180, n=4) but no functional characterization.	oncokb
PS4	Not assessed	No case-control or prevalence data available to assess enrichment of this variant in affected individuals versus controls.
PS5	Not met	No alternate pathogenic missense variant identified at amino acid residue His1380. PM5 candidate harvesting found no comparator variants at this position.	pm5_candidates
PM1	Not met	This variant does not lie within a statistically significant mutational hotspot in TET2.
PM2	Met	This variant is absent from all population databases, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Complete absence from large population cohorts supports a rare variant consistent with potential pathogenicity.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic missense comparator variants identified at the same amino acid residue (His1380) in ClinVar. PM5 candidate harvesting returned no same-residue candidates for comparison.	pm5_candidates
PM6	Not assessed	No de novo data available for this variant.
PP1	Not assessed	No cosegregation data available for this variant.
PP2	Not assessed	HCI prior data are not available for TET2; the rate of benign missense variation in this gene cannot be assessed. PP2 requires demonstration that the gene has a low rate of benign missense variation and that missense variants are a common disease mechanism.
PP3	Not met	Multiple in silico tools do not converge on a deleterious prediction. REVEL score is 0.657 (intermediate, below the 0.75 threshold for pathogenic prediction). BayesDel score is 0.120 (predicting benign). SpliceAI max delta score is 0.00 (no predicted splicing impact). The in silico evidence does not meet the threshold for multiple lines supporting a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	No patient-specific phenotypic data available to assess whether this variant is found in a patient with a phenotype highly specific for TET2-related disease.
PP5	Not met	This variant is absent from ClinVar and has not been classified by any reputable source or expert panel.	clinvar
BA1	Not met	BA1 requires an allele frequency above 1% in population databases. This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0.0).	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	BS1 requires an allele frequency above 0.3% in population databases. This variant is absent from all gnomAD cohorts (allele frequency 0.0).	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data on observation of this variant in healthy adults with full penetrance expected.
BS3	Not assessed	No variant-specific functional studies demonstrating no damaging effect on protein function or splicing.
BS4	Not assessed	No segregation data available to assess lack of cosegregation with disease.
BP1	Met	TET2 loss-of-function (truncating) variants are an established germline disease mechanism, associated with an autoimmune lymphoproliferative syndrome-like phenotype and hematologic malignancies (PMID:36066697, PMID:40031954). This variant is a missense substitution (p.His1380Pro) in a gene where primarily truncating variants are known to cause disease.	pvs1_gene_context
BP2	Not assessed	No data on observation of this variant in trans with a known pathogenic variant in a recessive disorder.
BP4	Met	Multiple lines of computational evidence suggest no significant impact on the gene product. BayesDel score is 0.120 (predicting benign). SpliceAI max delta score is 0.00 (no predicted splicing alteration). Although REVEL score is 0.657 (intermediate), two independent in silico methods converge on a benign or neutral prediction.	bayesdel spliceai revel
BP5	Not assessed	No data on an alternate molecular basis for disease that would rule out this variant as causative.
BP6	Not met	This variant is absent from ClinVar and has not been classified as benign by any reputable source.	clinvar
BP7	N/A	BP7 applies only to synonymous variants with no predicted splicing impact. This variant is a missense substitution (c.4139A>C, p.His1380Pro).
BP3	N/A	BP3 applies to in-frame insertions or deletions in repetitive regions. This variant is a single nucleotide substitution.
PM3	N/A	PM3 requires observation of the variant in trans with a known pathogenic variant for recessive disorders. No such data available and TET2 is not established as a recessive disease gene.
PM4	N/A	PM4 applies to protein length changes caused by in-frame insertions/deletions or stop-loss variants. This variant is a missense substitution.

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.