Variant classification summary

NM_001127208.2:c.4466dup

TET2 · NP_001120680.1:p.(Asn1489LysfsTer2) · NM_001127208.2

GRCh37: chr4:106193999 T>TA · GRCh38: chr4:105272842 T>TA

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.(Asn1489LysfsTer2)

gnomAD AF

6.447561338874798e-07 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001127208.2:c.4466dup (p.Asn1489LysfsTer2) is a frameshift duplication in exon 10 of TET2 predicted to trigger nonsense-mediated decay, meeting PVS1 at very strong strength.

2

This variant is extremely rare in population databases, absent from gnomAD v2.1 and gnomAD-Canada, with a single heterozygous observation in gnomAD v4.1 (1/1,550,974 alleles, AF = 0.000064%), meeting PM2 at supporting level.

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.4466dup is a frameshift duplication in exon 10 of 11, predicted to introduce a premature termination codon at p.(Asn1489LysfsTer2). NMD is expected as the PTC occurs well before the final exon (exon 11). TET2 loss of function is an established germline disease mechanism supported by literature (ALPS-like phenotype, hematologic malignancy). Under ClinGen SVI PVS1 framework (PMC6185798), frameshift variants in genes with established LOF disease mechanism are eligible for PVS1 at very strong strength.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies to same amino acid changes as established pathogenic missense variants; this is a frameshift duplication, not a missense variant.
PS2	N/A	No de novo evidence available for NM_001127208.2:c.4466dup in any literature or database.
PS3	Not met	No variant-specific functional studies identified for NM_001127208.2:c.4466dup. Reviewed full-text of PMID:21057493 and PMID:24315485; both provide general TET2 functional characterization (5hmC catalytic activity, crystal structure) but neither mentions this specific variant. OncoKB annotations are somatic-curated and do not substitute for germline functional evidence.
PS4	Not met	This variant is absent from ClinVar and COSMIC and has been observed only once in gnomAD v4.1 (1/1,550,974 alleles). No case reports or patient series link this variant to disease. PS4 requires statistically significant enrichment in affected individuals versus controls, which cannot be established from a single population allele.	gnomad_v4
PS5	N/A	PS5 applies to alternative missense or in-frame indel variants at the same amino acid position as an established pathogenic missense variant. NM_001127208.2:c.4466dup is a frameshift duplication.
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot. While TET2 has well-characterized functional domains (Cys-rich, DSBH catalytic domain), PM1 is not applied to truncating variants that are already evaluated under PVS1, as the domain-level evidence is redundant with the LOF assessment.
PM2	Met	NM_001127208.2:c.4466dup is absent from gnomAD v2.1 and gnomAD-Canada and is present at an extremely low frequency in gnomAD v4.1 (1/1,550,974 alleles, AF = 6.45e-07). This allele frequency is well below the PM2 threshold of 0.1% for a gene where TET2 LOF variants are associated with disease.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants. NM_001127208.2:c.4466dup is an out-of-frame (frameshift) duplication.
PM5	N/A	PM5 applies to novel missense variants at residues where different missense changes are known pathogenic. This is a frameshift duplication, not a missense variant. The PM5 candidate search confirmed not_applicable for this variant.
PM6	N/A	No de novo observation reported for NM_001127208.2:c.4466dup in any literature or database.
PP1	N/A	No family segregation data available for NM_001127208.2:c.4466dup.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This is a frameshift duplication, not a missense variant.
PP3	Not met	REVEL and BayesDel scores are unavailable for this duplication variant. SpliceAI predicts no significant splice impact (max delta = 0.14). No in silico prediction tools support a damaging effect at the protein level for this variant type.	spliceai
PP4	N/A	No patient phenotype or clinical data available for NM_001127208.2:c.4466dup.
PP5	Not met	This variant has not been reported by any reputable germline classification source. It is absent from ClinVar. OncoKB classifies it as Likely Oncogenic in a somatic context, which does not constitute a germline pathogenicity classification under PP5.	clinvar oncokb
BA1	Not met	NM_001127208.2:c.4466dup has an allele frequency of 6.45e-07 in gnomAD v4.1, far below the BA1 threshold of 1% in any population.	gnomad_v4
BS1	Not met	NM_001127208.2:c.4466dup has an allele frequency of 6.45e-07 in gnomAD v4.1, far below the BS1 threshold of 0.3% for dominant disorders.	gnomad_v4
BS2	Not met	Only one allele has been observed in gnomAD (v4.1), with no information on the clinical phenotype of that individual. This does not constitute observation in healthy adults at significant frequency.	gnomad_v4
BS3	Not met	No variant-specific functional studies are available for NM_001127208.2:c.4466dup. The two reviewed papers (PMID:21057493, PMID:24315485) characterize TET2 function generally but do not test this specific variant. OncoKB's somatic annotation does not constitute well-established functional evidence showing no damaging effect.
BS4	N/A	No family segregation data available for NM_001127208.2:c.4466dup.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_001127208.2:c.4466dup is itself a truncating (frameshift) variant.
BP2	N/A	No data on observation in trans with a pathogenic variant for NM_001127208.2:c.4466dup.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. NM_001127208.2:c.4466dup is an out-of-frame (frameshift) duplication.
BP4	Not met	REVEL and BayesDel are unavailable for this duplication variant. SpliceAI predicts no significant splice impact (max delta = 0.14). However, BP4 is intended for variants where multiple lines of computational evidence suggest no impact on gene product; the frameshift nature of this variant inherently predicts a deleterious effect on the protein. Available in silico evidence does not suggest benign impact.	spliceai
BP5	N/A	No data on co-occurrence with an alternate molecular basis for disease for NM_001127208.2:c.4466dup.
BP6	Not met	No reputable source has classified NM_001127208.2:c.4466dup as benign. The variant is absent from ClinVar. OncoKB classifies it as Likely Oncogenic (somatic), not benign.	clinvar oncokb
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_001127208.2:c.4466dup is a frameshift duplication, not a synonymous variant.

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.