NM_001127208.2:c.2152delC

TET2 · NP_001120680.1:p.(Leu718PhefsTer33) · NM_001127208.2

GRCh37: chr4:106157249 AC>A · GRCh38: chr4:105236092 AC>A

Gene: TET2 Transcript: NM_001127208.2

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

TET2

Transcript

NM_001127208.2

Protein

NP_001120680.1:p.(Leu718PhefsTer33)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001127208.2:c.2152delC is a frameshift deletion predicted to result in premature termination at codon 751 (p.Leu718PhefsTer33) in TET2, a gene for which heterozygous germline loss-of-function variants are an established cause of an autoimmune lymphoproliferative syndrome-like phenotype and hematologic malignancy.

This variant is absent from gnomAD population databases (v2.1 exomes, v4.1 exomes/genomes, and gnomAD-Canada v1.0), indicating it is not a common benign polymorphism and supporting evidence for rarity in the general population.

Under the generic ACMG/AMP 2015 classification framework, application of PVS1 (Very Strong) for a null variant in a gene where loss of function is a known disease mechanism, together with PM2 (Moderate) for absence from population databases, yields a Likely Pathogenic classification (1 Very Strong + 1 Moderate).

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.2152delC is a frameshift deletion predicted to produce premature termination at codon 751 (p.Leu718PhefsTer33). TET2 has an established loss-of-function disease mechanism for germline disease: heterozygous germline TET2 loss-of-function variants are associated with autoimmune lymphoproliferative syndrome-like phenotype and hematologic malignancy. The variant is in exon 3 of 11; the premature termination codon is >55 nucleotides upstream of the last exon-exon junction, so nonsense-mediated decay is expected. Under the ClinGen SVI PVS1 generic framework (PMC6185798), frameshift variants in genes with established LOF disease mechanism are assigned PVS1 at Very Strong strength.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 requires the same amino acid change as a previously established pathogenic variant. This is a frameshift deletion, not a single amino acid substitution at a specific residue.
PS2	Not met	No de novo occurrence of NM_001127208.2:c.2152delC has been reported, and maternity/paternity confirmation data are absent from all reviewed sources.
PS3	Not met	No well-established functional studies of NM_001127208.2:c.2152delC were identified. The two publications reviewed (PMID:21057493, PMID:24315485) describe general TET2 biochemical function and crystal structure but do not study this specific variant. OncoKB 'Likely Oncogenic' annotation is a somatic cancer database curation and does not constitute germline functional evidence.	oncokb
PS4	Not met	This variant is absent from gnomAD and ClinVar and has not been observed in affected individuals in any reviewed publication.
PS5	N/A	PS5 is for variants observed in trans with a pathogenic variant in recessive disorders. TET2 germline disease follows an autosomal dominant inheritance pattern (heterozygous LOF variants sufficient per PMID:40031954); no recessive disease model is established for TET2.
PM1	Not met	The variant at codon 718 lies N-terminal to the TET2 catalytic domain (residues 1129-1936) and is not located in a mutational hotspot or well-characterized critical functional domain free of benign variation. Hotspot analysis confirms this residue is not in a statistically significant hotspot.	pvs1_variant_assessment
PM2	Met	This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. Under generic ACMG/AMP standards, PM2 is met when a variant is absent from or at very low frequency (<0.1%) in population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 is for protein length changes due to in-frame deletions/insertions in non-repeat regions or stop-loss variants. This variant is an out-of-frame (frameshift) deletion resulting in premature termination, which is assessed under PVS1 rather than PM4.
PM5	N/A	PM5 requires a novel missense change at a residue where a different pathogenic missense change has been previously reported. This variant is a frameshift deletion, not a missense, and same-residue comparator semantics cannot be established from the normalized protein consequence.	pm5_candidates
PM6	Not assessed	No de novo observation of NM_001127208.2:c.2152delC has been reported with confirmed maternity and paternity in any reviewed publication or database.
PP1	Not met	No cosegregation data are available for this variant. No family studies were identified in the reviewed literature.
PP2	N/A	PP2 applies to missense variants in a gene with a low rate of benign missense variation and where missense variants are a common disease mechanism. This variant is a frameshift deletion, not a missense variant.
PP3	Not met	REVEL and BayesDel scores are not available for this deletion variant (not an SNV). SpliceAI predicts no significant splice impact (max delta score 0.04). No computational evidence supports a deleterious effect through in silico algorithms.	spliceai
PP4	Not met	No patient phenotype or clinical presentation data are available for review. This variant has not been reported in any individual in the reviewed literature.
PP5	Not met	No reputable clinical diagnostic laboratory has reported this variant as pathogenic. OncoKB 'Likely Oncogenic' is a somatic cancer database annotation and does not constitute a germline diagnostic classification from a reputable source.	oncokb
BA1	Not met	The variant is absent from gnomAD (allele frequency 0), which is far below the BA1 threshold of >1% population frequency.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD (allele frequency 0), which does not meet the BS1 threshold of >0.3% population frequency.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	BS2 is met when a variant is observed in a healthy adult individual for a disorder with full penetrance expected at an early age. The variant is absent from gnomAD (which includes largely healthy individuals), but absence alone does not satisfy BS2; BS2 requires observation in confirmed healthy individuals.
BS3	Not met	No well-established functional studies of NM_001127208.2:c.2152delC showing no damaging effect on protein function or splicing were identified in the reviewed literature.
BS4	Not met	No cosegregation data are available to demonstrate lack of segregation with disease in affected families.
BP1	N/A	BP1 applies to missense variants in genes for which primarily truncating variants are known to cause disease. This variant is a truncating frameshift variant, not a missense, and truncating variants are the established disease mechanism in TET2.
BP2	Not met	No evidence of this variant observed 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/insertions in repetitive regions without known function. This is an out-of-frame (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 gene or gene product. REVEL and BayesDel are not available for this deletion variant. SpliceAI shows no splice impact (max delta 0.04), but a single line of computational evidence targeting splicing alone is insufficient for BP4 when the variant's primary effect is protein truncation.	spliceai
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease has been reported.
BP6	Not met	No reputable source has reported this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This variant is a frameshift deletion, not a synonymous variant.

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