Variant classification summary

NM_001127208.2:c.2814_2815delTC

TET2 · NP_001120680.1:p.(Gln939AspfsTer32) · NM_001127208.2

GRCh37: chr4:106157911 ACT>A · GRCh38: chr4:105236754 ACT>A

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.(Gln939AspfsTer32)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001127208.2:c.2814_2815del (p.Gln939AspfsTer32) is a frameshift deletion in exon 3 of TET2 predicted to introduce a premature termination codon at residue 970, triggering nonsense-mediated decay. Under the ClinGen SVI generic PVS1 framework (PMC6185798), this qualifies for PVS1 at very strong strength, as TET2 loss of function is an established germline disease mechanism for autoimmune lymphoproliferative syndrome-like phenotype with hematologic malignancy.

2

This variant is absent from all queried population databases (gnomAD v2.1, v4.1, gnomAD-Canada), consistent with PM2 at supporting strength.

3

The variant is absent from ClinVar and has no variant-specific functional studies, case-control data, or segregation data in the literature. Two papers (PMID:21057493, PMID:24315485) characterize TET2 catalytic function and structure but do not mention this specific variant.

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.2814_2815del is a frameshift variant predicted to result in a premature termination codon at residue 970 (p.Gln939AspfsTer32) in exon 3 of 11 exons, well upstream of the last exon-exon junction, and is predicted to trigger nonsense-mediated decay. TET2 loss of function is established as a germline disease mechanism for an autoimmune lymphoproliferative syndrome-like phenotype with hematologic malignancy. Under the ClinGen SVI PVS1 framework (PMC6185798), this frameshift variant qualifies for PVS1 at very strong strength.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	This is a frameshift deletion, not a nucleotide substitution with a known pathogenic alternate at the same position.
PS2	Not assessed	No de novo data are available for this variant.
PS3	Not assessed	No variant-specific functional studies were identified. The available literature (PMID:21057493, PMID:24315485) discusses TET2 catalytic function and missense mutations in myeloid malignancies but does not include NM_001127208.2:c.2814_2815delTC.
PS4	Not assessed	No case-control or prevalence data are available for this variant.
PS5	N/A	This variant is absent from ClinVar and no expert panel or reputable source has classified it as pathogenic.
PM1	Not met	This variant is located in exon 3, encoding the N-terminal region of TET2 (codon 939 of 2003), upstream of the well-characterized C-terminal catalytic domain (Cys-rich and DSBH domains, approximately residues 1129-1936). Hotspot analysis confirms no statistically significant mutational hotspot at this position.
PM2	Met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, consistent with PM2 under generic ACMG/AMP criteria (allele frequency <0.1% in all populations).	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Skipped: PM3 applies to recessive disorders; TET2-related germline disease follows autosomal dominant/heterozygous LoF mechanism.
PM4	N/A	This frameshift variant is already assessed under PVS1. Applying PM4 would constitute double-counting of the same protein-truncation evidence per ACMG/AMP 2015 guidance.
PM5	N/A	This is a frameshift variant. PM5 applies to novel missense variants at a residue where a different pathogenic missense change has been established; no same-residue missense comparator is applicable.
PM6	Not assessed	No de novo data are available for this variant.
PP1	Not assessed	No segregation data are available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This is a frameshift variant.
PP3	Not met	SpliceAI predicts no significant splice impact (max delta score 0.06, well below the 0.2 threshold). REVEL and BayesDel scores are not available for this deletion variant. No computational evidence supports a deleterious effect.	spliceai
PP4	Not assessed	No patient-specific phenotype data are available for this variant.
PP5	N/A	This variant is absent from ClinVar and has not been classified as pathogenic by any expert panel or reputable source.
BA1	Not met	This variant is absent from gnomAD population databases; allele frequency is 0%, far below the BA1 threshold of >5%.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD; allele frequency is 0%, below the BS1 threshold of >0.3% for non-VCEP assessment.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data are available on observation of this variant in healthy adults.
BS3	Not assessed	No variant-specific functional studies demonstrating no deleterious effect were identified. The available literature (PMID:21057493, PMID:24315485) addresses TET2 general function and missense mutations but does not include this frameshift variant.
BS4	Not assessed	No segregation data are available for this variant.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants cause disease. This is a truncating (frameshift) variant.
BP2	Not assessed	No data are available on observation of this variant in trans with a pathogenic variant.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions. This is a frameshift deletion, not an in-frame variant.
BP4	Not met	SpliceAI predicts no splice impact (max delta 0.06), but REVEL and BayesDel scores are not available for this deletion. A single benign computational prediction is insufficient to meet BP4, which requires multiple lines of computational evidence suggesting no impact.	spliceai
BP5	Not assessed	No data are available on observation of this variant in a case with an alternate molecular cause.
BP6	N/A	This variant is absent from ClinVar; no reputable source has classified it as benign.
BP7	N/A	BP7 applies to silent (synonymous) variants with no predicted splice impact. This is a frameshift deletion.

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