NM_001127208.2:c.822del

TET2 · NP_001120680.1:p.(Asn275IlefsTer18) · NM_001127208.2

GRCh37: chr4:106155920 TC>T · GRCh38: chr4:105234763 TC>T

Gene: TET2 Transcript: NM_001127208.2

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

TET2

Transcript

NM_001127208.2

Protein

NP_001120680.1:p.(Asn275IlefsTer18)

gnomAD AF

1.6731589364658174e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001127208.2:c.822del is a frameshift deletion in exon 3 of TET2, predicted to cause a premature termination codon (p.Asn275IlefsTer18) with expected nonsense-mediated decay, meeting PVS1 at very strong strength. TET2 loss-of-function is an established germline disease mechanism associated with ALPS-like phenotype and hematologic malignancy susceptibility.

This variant is present in gnomAD at extremely low frequency (AF=0.00167% in v4.1, 0.00160% in v2.1; no homozygotes), meeting PM2 at supporting strength.

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00), but REVEL and BayesDel are not available for this deletion variant, so PP3 is not met.

This variant has been reported as Pathogenic in ClinVar by a single clinical laboratory (1-star review status). PP5 requires a 3-star expert panel review and is not met. The variant is absent from COSMIC as a somatic observation? No: COSMIC reports this variant in n=30 somatic cancer samples (COSV54404867). OncoKB classifies the variant as Likely Oncogenic with Likely Loss-of-function effect.

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	Met	NM_001127208.2:c.822del is a frameshift variant in exon 3 of 11, predicted to cause a premature termination codon at position 292 (NP_001120680.1:p.(Asn275IlefsTer18)) with expected nonsense-mediated decay. TET2 has an established loss-of-function disease mechanism in the germline context, associated with an ALPS-like phenotype and hematologic malignancy susceptibility. Under ClinGen SVI PVS1 recommendations (PMC6185798), a null variant in a gene where LOF is a known mechanism of disease meets PVS1 at very strong strength.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 applies to variants producing the same amino acid substitution as a known pathogenic missense change. This variant is a frameshift deletion, not an amino acid substitution.
PS2	Not met	PS2 requires a confirmed de novo occurrence with both maternity and paternity confirmed. No de novo data are available for this variant.
PS3	Not met	PS3 requires variant-specific functional evidence. Two TET2 functional studies were reviewed in full text (PMID:21057493, PMID:24315485); neither tested c.822del or a systematically characterized range that includes codon 275. These papers demonstrate that TET2 catalytic domain mutations impair 5mC oxidation, but domain-level inference from sparse mutagenesis does not satisfy PS3's requirement for direct variant testing or systematic range characterization. The functional consequence of this frameshift variant is inferred from its null nature (PVS1), not from experimental data.
PS4	Not met	PS4 requires the variant prevalence in affected individuals to be significantly increased compared to controls. The variant has been reported in ClinVar by a single clinical laboratory (Invitae) as Pathogenic, and PMID:36066697 reports germline TET2 mutations in two patients with ALPS-like phenotype, but the abstract does not specify whether c.822del is among the variants described. Full text of PMID:36066697 is not available for confirmation. Without access to case-level data or case-control statistics, PS4 cannot be met.	clinvar
PS5	N/A	PS5 applies to novel missense variants at a residue where a different missense change has been determined to be pathogenic. This variant is a frameshift deletion, not a missense variant.
PM1	Not met	PM1 requires location in a critical functional domain or mutational hotspot. The variant causes a frameshift at codon 275 in the N-terminal region of TET2, well upstream of the catalytic domain (aa 1129-1936). The variant creates a PTC with expected NMD, so the mechanism is complete loss of protein expression rather than domain-specific disruption. The codon 275 position is not in a statistically significant mutational hotspot (cancerhotspots.org) and is not within a characterized functional domain. The loss-of-function effect is already captured by PVS1.
PM2	Met	This variant is present in gnomAD at extremely low frequency (v2.1: AF=0.0016%, 4/250,288 alleles; v4.1: AF=0.00167%, 27/1,613,714 alleles; highest subpopulation AF=0.00327% in South Asian, gnomAD v2.1). This frequency is well below the 0.1% threshold for PM2 under generic ACMG/AMP rules. No homozygotes have been observed.	gnomad_v2 gnomad_v4
PM4	N/A	PM4 applies to non-repeat in-frame deletions/insertions or stop-loss variants causing protein length changes. This variant is a frameshift deletion, not an in-frame change.
PM5	N/A	PM5 requires a novel missense variant at a residue where another missense change is known to be pathogenic. This is a frameshift variant; PM5 semantics cannot be applied. The pm5_candidates module confirmed this variant is not eligible for classic PM5 assessment.	pm5_candidates
PM6	Not met	PM6 requires an assumed de novo occurrence without confirmation of paternity and maternity. No de novo data are available for this variant.
PP1	Not met	PP1 requires co-segregation of the variant with disease in multiple affected family members. No segregation data are available for this variant.
PP2	Not met	PP2 applies to missense variants in genes where missense variation is the primary pathogenic mechanism and benign missense variation is rare. TET2 disease mechanism is loss-of-function via truncating variants, and this variant is itself a frameshift deletion, not a missense substitution. PP2 does not apply.
PP3	Not met	PP3 requires multiple lines of computational evidence supporting a deleterious effect. REVEL and BayesDel scores are not available for this deletion variant. SpliceAI predicts no significant splice impact (max delta score = 0.00). The HCI prior is not available for TET2. No multiple lines of in silico evidence are available.	spliceai
PP4	Not met	PP4 requires a patient phenotype or family history highly specific for a disease with a single genetic etiology. No patient phenotype or family history data are available in this case.
PP5	Not met	PP5 requires a reputable source to have classified the variant as pathogenic with supporting evidence. This variant is classified as Pathogenic in ClinVar (variation ID 1936676) by a single clinical laboratory (Invitae) with review status 'criteria provided, single submitter' (1-star). Under the adjudication framework, PP5 at supporting strength requires a ClinVar 3-star expert panel review status, which is not met.	clinvar
BA1	Not met	BA1 requires an allele frequency >1% in population databases. This variant has a maximum population AF of 0.00327% in the South Asian population (gnomAD v2.1), and an overall AF of 0.0016-0.0017%, far below the 1% threshold.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 requires an allele frequency >0.3% in population databases. This variant has a maximum population AF of 0.00327%, well below the 0.3% threshold.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires observation of the variant in a healthy adult individual for a disorder with full penetrance expected at an early age, in the appropriate zygosity state. No such observation data are available.
BS3	Not met	BS3 requires well-established functional studies showing no damaging effect. The available functional literature (PMID:21057493, PMID:24315485) demonstrates that TET2 mutations impair catalytic function, and OncoKB classifies this variant as Likely Loss-of-function. No studies suggest a benign functional effect.
BS4	Not met	BS4 requires lack of segregation of the variant with disease in affected family members. No segregation data are available.
BP1	Not met	BP1 applies to missense variants in genes where primarily truncating variants cause disease. This is itself a truncating (frameshift) variant, not a missense change. BP1 does not apply to the variant type it is designed to contrast against.
BP2	Not met	BP2 requires observation of the variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern. No such data are available.
BP3	Not met	BP3 applies to in-frame deletions or insertions in repetitive regions without known function. This variant is a frameshift deletion, not an in-frame change in a repetitive region.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on the gene product. REVEL and BayesDel are not available for this deletion variant. SpliceAI shows no splice impact (max delta = 0.00), but this single line of evidence is insufficient for BP4. Additionally, the frameshift nature of the variant is inherently damaging and inconsistent with a benign computational prediction.	spliceai
BP5	Not met	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data are available.
BP6	Not met	BP6 requires a reputable source to have classified the variant as benign. This variant is classified as Pathogenic in ClinVar, not Benign. BP6 is not met.	clinvar
BP7	Not met	BP7 applies to synonymous variants with no predicted splice impact and low nucleotide conservation. This variant is a frameshift deletion, not a synonymous substitution.

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