NM_001127208.2:c.4354C>T

TET2 · NP_001120680.1:p.(Arg1452Ter) · NM_001127208.2

GRCh37: chr4:106193892 C>T · GRCh38: chr4:105272735 C>T

Gene: TET2 Transcript: NM_001127208.2

Final call

Likely Pathogenic

PVS1 strong PM1 moderate PM2 supporting

Variant details

Gene

TET2

Transcript

NM_001127208.2

Protein

NP_001120680.1:p.(Arg1452Ter)

gnomAD AF

9.668063164679343e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001127208.2:c.4354C>T (p.Arg1452Ter) is a nonsense variant in exon 10 of 11 of TET2, predicted to result in nonsense-mediated decay and loss of protein function.

TET2 germline loss-of-function mutations are associated with an ALPS-like immune dysregulation syndrome and predisposition to hematologic malignancy, with heterozygous LoF variants reported to cause disease in multiple families.

This variant has been observed in gnomAD at extremely low frequency (v2.1: 2/156592 alleles, AF=0.00128%; v4.1: 15/1551500 alleles, AF=0.00097%) with no homozygotes, and is absent from gnomAD-Canada.

The variant truncates the protein at residue 1452 within the catalytic domain (residues 1129-1936), removing critical functional regions including the DSBH core, Fe(II)-chelating site (H1881), 2OG-interacting residues (R1896), and DNA-interacting loops.

This variant has been observed in COSMIC as a somatic mutation (27 entries) and reported in ClinVar with conflicting classifications (one VUS, one Pathogenic, single submitters with no expert panel review).

No variant-specific functional studies, de novo reports, segregation data, or case-control studies were identified for c.4354C>T in the reviewed literature.

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 (c.4354C>T, p.Arg1452Ter) predicted to result in premature termination and nonsense-mediated decay (NMD) in a gene where loss of function is an established germline disease mechanism. The variant is located in exon 10 of 11 and is not predicted to escape NMD. TET2 germline loss-of-function mutations are associated with an ALPS-like immune dysregulation syndrome with predisposition to hematologic malignancy (PMID:36066697, PMID:40031954). Under PMC6185798, nonsense variants in genes with established LoF disease mechanism qualify for PVS1 at full strength when not in the terminal exon.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework PMID:36066697
PS1	N/A	PS1 applies to missense variants where the same amino acid change has been observed as pathogenic via a different nucleotide change. This variant is a nonsense (stop-gain) change, not a missense.
PS2	Not assessed	No de novo report was identified for NM_001127208.2:c.4354C>T. The available literature describes de novo occurrence of different TET2 variants (e.g., p.Gly93Ter in PMID:36066697) but not this specific variant. Without a confirmed de novo observation, PS2 cannot be applied.
PS3	Not met	No variant-specific functional data or systematic range characterization covering position Arg1452 was identified in the literature. The functional studies reviewed (PMID:21057493, PMID:24315485) characterized TET2 catalytic activity and crystal structure but tested different residues and did not assess the effect of truncation at position 1452. OncoKB curation labels this variant as 'Likely Loss-of-function' based on the nonsense mechanism, not variant-specific experimental evidence. Without direct functional testing or systematic range characterization that includes this variant position, PS3 is not met.	PMID:21057493 PMID:24315485 oncokb
PS4	Not met	The variant has been observed in gnomAD at extremely low frequency (v2.1: 2/156592; v4.1: 15/1551500 alleles) and reported in ClinVar with conflicting classifications (one VUS, one Pathogenic, single submitters only). COSMIC reports 27 somatic occurrences but these are not germline cases. No case-control study or statistically significant enrichment in affected individuals has been demonstrated. The PMID:36066697 paper describes germline TET2 disease but reports different variants (p.Gly93Ter, p.Asn598IlefsTer3, 4q24del), not c.4354C>T.	gnomad_v2 gnomad_v4 clinvar PMID:36066697
PS5	Not met	No reputable source has recently reported this variant as pathogenic. ClinVar contains two single-submitter classifications (one VUS, one Pathogenic) with no expert panel review. This does not satisfy the PS5 requirement for a recently established pathogenic classification from a reputable source.	clinvar
PM1	Met	The variant truncates the TET2 protein at position 1452, which lies within the catalytic domain (residues 1129-1936 as defined by PMID:24315485). The truncation removes the DSBH core and C-terminal catalytic machinery including Fe(II)-chelating residues (H1881), 2OG-interacting residues (R1896), and DNA-interacting loops. The catalytic domain is a well-characterized functional domain critical for TET2's 5-methylcytosine dioxygenase activity. Truncating variants that remove this domain abrogate TET2 enzymatic function.	PMID:24315485 PMID:21057493 pvs1_variant_assessment
PM2	Met	This variant is present in gnomAD at extremely low allele frequency: v2.1 AF=1.28e-5 (0.00128%, 2/156592 alleles), v4.1 AF=9.67e-6 (0.00097%, 15/1551500 alleles), well below the 0.1% threshold for PM2. It is absent from gnomAD-Canada. No homozygotes have been observed in any population database.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 applies to missense variants at the same residue where a different pathogenic missense change has been observed. This variant is a nonsense (stop-gain), and no same-residue comparator candidates were identified by the automated PM5 candidate search.	pm5_candidates
PM6	Not assessed	No de novo report was identified for NM_001127208.2:c.4354C>T in the reviewed literature. The PMID:36066697 paper describes a different variant (p.Gly93Ter) as de novo but does not report de novo occurrence of c.4354C>T. Without a confirmed de novo observation of this specific variant, PM6 cannot be applied.
PP1	Not met	No co-segregation data is available for this variant. None of the reviewed publications report familial segregation analysis involving NM_001127208.2:c.4354C>T.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This variant is a nonsense (stop-gain), not a missense variant.
PP3	Not met	Computational evidence does not support a deleterious effect for this variant. SpliceAI predicts no significant splice impact (max delta score = 0.16). BayesDel score is 0.558747 (borderline, not strongly pathogenic). REVEL and HCI prior scores are unavailable. There is no consensus from multiple in silico tools supporting a deleterious effect.	spliceai bayesdel
PP4	Not assessed	Insufficient phenotype data is available for patients carrying this variant. ClinVar submissions list conditions as 'Not Provided' (GeneDx) or provide no condition labels (Invitae). Without a specific patient phenotype that matches the TET2-associated disease spectrum, PP4 cannot be assessed.	clinvar
PP5	Not met	No reputable source has definitively classified this variant as pathogenic. ClinVar contains two single-submitter classifications (one VUS by GeneDx, one Pathogenic by Invitae) with no expert panel review. The conflicting classifications and absence of expert panel consensus do not meet PP5 requirements.	clinvar
BA1	Not met	The maximum allele frequency in gnomAD is 1.28e-5 (0.00128%) in v2.1 and 9.67e-6 (0.00097%) in v4.1, both well below the BA1 threshold of 1% (and adjusting AF). The variant is too rare to be considered a common polymorphism.	gnomad_v2 gnomad_v4
BS1	Not met	The maximum allele frequency in gnomAD (0.00128% in v2.1, 0.00097% in v4.1) is well below the BS1 threshold of 0.3%. The variant is too rare in population databases to be considered benign.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous individuals have been observed in any population database (gnomAD v2.1: 0 homozygotes out of 156592 alleles; gnomAD v4.1: 0 homozygotes out of 1551500 alleles). The variant is not observed in a homozygous state in healthy adults, so BS2 does not apply.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrate a benign effect for this variant. The reviewed functional literature (PMID:21057493, PMID:24315485) characterizes TET2 catalytic activity and structure but does not include R1452*. The evidence, though indirect, is consistent with loss of function (truncation of catalytic domain), not a benign effect.	PMID:21057493 PMID:24315485
BS4	Not met	No segregation data is available for this variant. No family studies demonstrate lack of co-segregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. This variant is itself a truncating (nonsense) variant.
BP2	Not assessed	No data is available regarding observation of this variant in trans with a known pathogenic variant. This information would require clinical testing data not present in the case materials.
BP4	Not met	Computational evidence does not support a benign effect. BayesDel score is 0.559 (borderline, not clearly benign). SpliceAI shows no significant splice impact but this is neutral, not benign. REVEL is unavailable. No consensus from multiple in silico tools indicates a benign effect.	spliceai bayesdel
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease is available. The required evidence (variant found in individual with a different confirmed genetic cause for the same phenotype) is absent.
BP6	Not met	This variant is not classified as Benign or Likely Benign by a reputable source. ClinVar shows classifications of VUS and Pathogenic, not benign. BP6 requires a benign classification from a reputable source with evidence sharing.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) or intronic variants without predicted splice impact at non-conserved positions. This variant is a nonsense (stop-gain) variant, not synonymous or intronic.

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