NM_001127208.2:c.5456T>G

TET2 · NP_001120680.1:p.(Leu1819Ter) · NM_001127208.2

GRCh37: chr4:106197123 T>G · GRCh38: chr4:105275966 T>G

Gene: TET2 Transcript: NM_001127208.2

Final call

VUS

PM2 moderate

Variant details

Gene

TET2

Transcript

NM_001127208.2

Protein

NP_001120680.1:p.(Leu1819Ter)

gnomAD AF

1.2889388424298044e-06 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The TET2 c.5456T>G (p.Leu1819Ter) variant has not been reported in ClinVar, and curated oncology resources identify variant-specific literature context consistent with somatic relevance.

This variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at 2/1,551,664 alleles (AF 0.00013%; highest population AF 0.00017%), which is below the 0.1% PM2 threshold and far below benign-frequency thresholds.

Published TET2 studies support the biological importance of TET2 loss of function, but no variant-specific functional assay for p.(Leu1819Ter) was identified.

This nonsense change occurs in the last exon, SpliceAI predicts no significant splice impact (max delta score 0.00), REVEL was unavailable, and BayesDel score 0.288612 does not independently resolve pathogenicity for this 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	Not assessed	Germline loss of function is supported as a disease mechanism for TET2, and this variant is a nonsense change. However, c.5456T>G (p.Leu1819Ter) lies in the last exon and is predicted to truncate the final 184 of 2003 amino acids (about 9.2%), so additional review is needed to determine whether loss of this distal C-terminal region is sufficient for a generic PVS1 strength assignment.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No previously established pathogenic variant causing the same amino acid change was identified in the reviewed sources.	clinvar
PS2	Not assessed	No de novo occurrence data with confirmed maternity and paternity were identified for this variant.	clinvar
PS3	Not assessed	Published studies and curated oncology resources support that loss of TET2 function is biologically relevant, but no variant-specific functional assay for p.(Leu1819Ter) was identified, so PS3 cannot be applied from the current evidence.	oncokb PMID:21057493 PMID:24315485
PS4	Not assessed	No case-control data or clear enrichment of this exact variant in affected individuals were identified.	clinvar gnomad_v4
PM1	Not met	Available hotspot review did not identify this variant in a statistically significant hotspot or other well-established critical region without benign variation.	hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 2/1,551,664 alleles (AF 0.00013%; highest population AF 0.00017%; grpmax FAF 2.9e-07), which is below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4
PM3	N/A	No recessive inheritance context or trans observations relevant to PM3 were identified for this variant.
PM4	N/A	This is a nonsense variant rather than an in-frame length change, so PM4 is not the appropriate criterion.	pvs1_variant_assessment
PM5	N/A	Classic same-residue PM5 logic could not be confirmed safely for this case, and no validated comparator variants were identified for application of PM5.	pm5_candidates
PM6	Not assessed	No assumed de novo report for this variant was identified.	clinvar
PP1	Not assessed	No segregation data in affected relatives were identified for this variant.	clinvar
PP2	N/A	This criterion is intended for missense variation in genes with a low rate of benign missense variation and a common pathogenic missense mechanism. This variant is a nonsense change.
PP3	Not met	Computational evidence does not independently support a damaging effect beyond the known stop-gain consequence. SpliceAI predicts no significant splice impact (max delta score 0.00), REVEL was unavailable, and BayesDel score 0.288612 alone is not sufficient to apply PP3 for this nonsense variant.	spliceai bayesdel
PP4	Not assessed	No patient-specific phenotype information was provided to assess whether the clinical presentation is highly specific for a TET2-related disorder.
PP5	Not assessed	No pathogenic assertion from a reputable external clinical source was identified in the reviewed materials, and the variant is absent from ClinVar.	clinvar
BA1	Not met	The observed population frequency does not meet the benign stand-alone threshold. In gnomAD v4.1 the total AF is 0.00013%, which is well below the 1.0% BA1 threshold.	gnomad_v4
BS1	Not met	The observed population frequency does not meet the strong benign threshold. In gnomAD v4.1 the total AF is 0.00013%, which is well below the 0.3% BS1 threshold.	gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals in a context sufficient to support BS2.	gnomad_v4
BS3	Not assessed	No well-established functional study demonstrating a normal or benign effect for this exact variant was identified.	oncokb PMID:21057493 PMID:24315485
BS4	Not assessed	No family data showing lack of segregation with disease were identified for this variant.	clinvar
BP1	N/A	This criterion applies to missense variants in genes where truncating variants are the predominant pathogenic mechanism. This variant is a nonsense change.
BP2	Not assessed	No cis/trans phase data with another variant were identified for this case.
BP3	Not assessed	No evidence was identified that this variant lies in a repetitive region without known function.
BP4	Not met	Computational evidence does not support a benign effect. SpliceAI predicts no significant splice impact (max delta score 0.00), but REVEL was unavailable and BayesDel score 0.288612 does not provide benign support for this stop-gain variant.	spliceai bayesdel
BP5	Not assessed	No alternate molecular explanation was identified that would account for the phenotype independently of this variant.
BP6	Not assessed	No reputable benign classification for the exact variant was identified, and the variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 applies to synonymous or certain intronic variants with no predicted splice impact. This variant is a nonsense change.	spliceai

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.