Variant classification summary

NM_001127208.2:c.5481del

TET2 · NP_001120680.1:p.(Lys1827AsnfsTer6) · NM_001127208.2

GRCh37: chr4:106197147 AG>A · GRCh38: chr4:105275990 AG>A

Gene: TET2 Transcript: NM_001127208.2

Final call

Likely Pathogenic

PVS1 strong PM2 moderate

Variant details

Gene

TET2

Transcript

NM_001127208.2

Protein

NP_001120680.1:p.(Lys1827AsnfsTer6)

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1_Strong: NM_001127208.2:c.5481del is a frameshift deletion (p.Lys1827AsnfsTer6) in TET2, a gene where germline loss of function is an established disease mechanism for ALPS-like immunodeficiency and hematologic malignancy predisposition. The variant resides in the terminal exon (exon 11/11) and is predicted to escape nonsense-mediated decay; strength is downgraded from PVS1 to PVS1_Strong per PMC6185798.

2

PM2: Variant is entirely absent from gnomAD v4.1 (0/1,551,736 alleles, AF=0.0000%) and gnomAD v2.1, meeting the PM2 threshold for extremely low population frequency.

3

No additional pathogenic or benign criteria were met. PS3 (functional evidence) and BS3 (benign functional evidence) could not be assessed as no variant-specific functional studies for NM_001127208.2:c.5481del were identified in the reviewed literature (PMID:21057493, PMID:24315485).

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	NM_001127208.2:c.5481del is a frameshift deletion in exon 11 (the terminal exon) of TET2, predicted to cause p.Lys1827AsnfsTer6, a premature termination codon truncating the protein from 2003 to 1832 amino acids with loss of approximately 176 C-terminal residues. TET2 loss of function is a well-established germline disease mechanism (ALPS-like phenotype, hematologic malignancy predisposition). Under PMC6185798 (ClinGen SVI PVS1 recommendations), a null variant in a gene with established LOF disease mechanism qualifies for PVS1 at very strong level; however, because the variant resides in the terminal exon and is predicted to escape nonsense-mediated decay, the strength is downgraded to PVS1_Strong.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies when the variant is an amino acid change at the same position as a known pathogenic missense variant. NM_001127208.2:c.5481del is a frameshift deletion, not a missense variant.
PS2	Not met	No de novo evidence for this variant was identified. Neither the literature search nor ClinVar submissions report a de novo occurrence of NM_001127208.2:c.5481del.
PS3	Not assessed	No variant-specific functional studies for NM_001127208.2:c.5481del (p.Lys1827AsnfsTer6) were identified. Two papers (PMID:21057493, PMID:24315485) report general TET2 functional characterization but neither mentions this specific variant. OncoKB classifies the variant as Likely Oncogenic in a somatic context based on general TET2 LOF biology, not variant-specific functional assays.	oncokb
PS4	Not met	The variant is entirely absent from gnomAD v2.1, gnomAD v4.1 (0/1,551,736 alleles), and gnomAD-Canada. No case-control studies or cohort enrichment data are available to demonstrate a statistically significant excess in affected individuals.	gnomad_v2 gnomad_v4 gnomad_canada
PS5	N/A	PS5 is not applicable because PS1 (the prerequisite for PS5) does not apply to this frameshift deletion variant.
PM1	Not met	Residue 1827 does not lie in a statistically significant cancer hotspot. While the variant falls within the TET2 catalytic domain (C-terminal DSBH domain, residues ~1129-1936), absence of a recognized mutational hotspot at this position precludes application of PM1.
PM2	Met	NM_001127208.2:c.5481del is entirely absent from gnomAD population databases: absent from v2.1 exomes, v4.1 exomes (0/1,399,432 alleles) and genomes (0/152,304 alleles), combined 0/1,551,736 alleles (AF=0.0000%). This meets the PM2 threshold for extremely low or absent population frequency (<0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 addresses protein length changes from in-frame deletions/insertions or stop-loss variants. NM_001127208.2:c.5481del is a frameshift deletion causing a premature termination codon; the null variant mechanism is already assessed under PVS1.
PM5	N/A	PM5 requires a known pathogenic missense variant at the same amino acid residue. NM_001127208.2:c.5481del is a frameshift deletion, not a missense change. The PM5 candidates analysis confirmed that classic same-residue PM5 semantics cannot be applied to this variant.	pm5_candidates
PM6	Not met	No de novo evidence was identified. PM6 requires a confirmed de novo occurrence with both maternity and paternity confirmed. No such reports exist for this variant in ClinVar or the reviewed literature.
PP1	Not met	No segregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members.
PP2	N/A	PP2 applies specifically to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. NM_001127208.2:c.5481del is a frameshift deletion, not a missense variant.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splice impact (max delta score = 0.00). REVEL and BayesDel scores are not available for this non-SNV variant. No additional computational evidence supports pathogenicity for this frameshift deletion.	spliceai
PP4	Not met	No patient phenotype or family history data are available for this variant. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The proband's clinical presentation is unknown.
PP5	Not met	No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar entirely, and no expert panel or clinical laboratory has reported it.	clinvar
BA1	Not met	The variant is entirely absent from gnomAD (0/1,551,736 alleles, AF=0.0000%), far below the BA1 threshold of >1% population frequency.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is entirely absent from gnomAD (0/1,551,736 alleles, AF=0.0000%), far below the BS1 threshold of >0.3% population frequency.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observations have been reported in any population database. BS2 requires observation in a healthy adult individual in a homozygous state, or in trans with a known pathogenic variant, with full penetrance expected at an early age.	gnomad_v4
BS3	Not assessed	No variant-specific functional studies demonstrating a benign effect were identified. The two reviewed publications (PMID:21057493, PMID:24315485) report general TET2 structural and functional characterization but do not mention NM_001127208.2:c.5481del. BS3 cannot be assessed without variant-level functional data showing no deleterious impact.
BS4	Not met	No evidence of lack of segregation is available. BS4 requires observation of the variant in a family member who does not have the disease phenotype or lack of cosegregation in multiple affected family members.
BP1	N/A	BP1 applies to missense variants in a gene where a different pathogenic missense change at the same residue has been established. NM_001127208.2:c.5481del is a frameshift deletion, not a missense variant.
BP2	Not met	No observation of this variant in trans with a known pathogenic variant has been reported. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions without known function. NM_001127208.2:c.5481del is a frameshift deletion, not an in-frame indel.
BP4	Not met	Multiple lines of computational evidence do not support a benign impact. SpliceAI predicts no splice effect (max delta = 0.00), but this is neutral rather than positively benign. No other in silico scores are available for this non-SNV variant. BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product.	spliceai
BP5	Not met	No alternative molecular basis for disease has been identified in this case. BP5 requires a variant found in a case with an alternate molecular basis for disease.
BP6	Not met	No reputable source has classified this variant as benign. The variant is absent from ClinVar entirely.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_001127208.2:c.5481del is a frameshift deletion, not a synonymous variant.

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