NM_002168.3:c.413C>A

IDH2 · NP_002159.2:p.(Thr138Asn) · NM_002168.3

GRCh37: chr15:90631940 G>T · GRCh38: chr15:90088708 G>T

Gene: IDH2 Transcript: NM_002168.3

Final call

VUS

PM2 supporting

Variant details

Gene

IDH2

Transcript

NM_002168.3

Protein

NP_002159.2:p.(Thr138Asn)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): c.413C>A is absent from gnomAD v2.1 exomes, gnomAD v4.1 exomes, and gnomAD-Canada v1.0 genomes (germline allele frequency 0).

Variant of Uncertain Significance: the single supporting criterion (PM2) satisfies no ACMG/AMP 2015 Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination threshold.

Final determination: Generic ACMG/AMP 2015 fallback combination rule: with only 1 supporting criterion (PM2) met and no PVS1/PS/PM/PP pathogenic combination and no BA1/BS/BP benign combination threshold satisfied, 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	N/A	Not applicable: this is a missense change, and PVS1 applies only to null variants (nonsense, frameshift, or splice-site) expected to abolish protein function.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no pathogenic variant producing p.Thr138Asn is documented in ClinVar, the literature, or OncoKB — the only same-amino-acid report is a single somatic COSMIC occurrence.	clinvar oncokb generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband phenotype, parental testing, or trio data were available, so a confirmed de novo occurrence could not be evaluated.	clinvar generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no variant-specific functional studies exist; OncoKB lists this variant as 'Unknown Oncogenic Effect' with no reviewed functional evidence.	oncokb
PS4	Not assessed	Not assessed: no case-control or cohort data exist; the only observation is a single somatic COSMIC occurrence, which cannot support PS4.	clinvar
PM1	Not met	Not met: T138 is not a documented mutational hotspot — CancerHotspots lists no significant hotspot at this residue — and the established IDH2 hotspots are R140 and R172.	clinvar generic_acmg_combination_rules
PM2	Met	Met (supporting): absent from gnomAD v2.1 exomes, v4.1 exomes, and gnomAD-Canada v1.0 genomes, with germline allele frequency 0.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no second allele, phase, or segregation data exist — the variant is absent from ClinVar and gnomAD — so trans/cis status is unevaluable.
PM4	N/A	Not applicable: this missense change does not alter protein length, and PM4 applies only to in-frame indels or stop-loss extensions.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: no different missense change at residue 138 is documented as pathogenic. Flagged for human review: a full ClinVar enumeration of residue-138 changes was not performed.	pm5_candidates clinvar generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no parental or family genotype data exist, so an assumed de novo origin could not be evaluated.	clinvar generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no family segregation data are available — no affected relatives genotyped and no external segregation reports.	clinvar pvs1_gene_context generic_acmg_combination_rules
PP2	Not assessed	Not assessed: IDH2's rate of benign missense variation could not be established from any consulted source.	oncokb pvs1_gene_context generic_acmg_combination_rules
PP3	Not met	Not met: REVEL 0.736 is below the >=0.932 PP3 threshold, and SpliceAI max delta 0.00 predicts no splice impact.	spliceai revel bayesdel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family history was provided, so phenotype specificity could not be evaluated.
PP5	N/A	Not applicable: ClinVar has no record for this variant, so no expert-panel pathogenic assertion exists to apply.	clinvar
BA1	Not met	Not met: germline allele frequency is 0 across gnomAD v2.1, v4.1, and gnomAD-Canada — far below the >5% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: the variant is absent from all gnomAD datasets (allele frequency 0), which is not greater than expected for any disease model.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS2	Not met	Not met: the variant is not observed in any healthy-individual dataset — absent from gnomAD and ClinVar.	gnomad_v2 gnomad_v4 gnomad_canada clinvar
BS3	Not assessed	Not assessed: no functional studies demonstrating a lack of damaging effect exist; OncoKB reports no reviewed functional evidence for this variant.	oncokb
BS4	Not assessed	Not assessed: no genotyped family members exist, so lack of segregation in affected relatives could not be evaluated.	clinvar gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BP1	Not met	Not met: missense variants are an established IDH2 disease mechanism (cancer hotspots R140/R172), so the truncating-only premise fails.	oncokb pvs1_gene_context generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no observation of this variant with any other variant, and no phase information, exists in any dataset.
BP3	N/A	Not applicable: this missense change does not alter protein length in a repetitive region, which BP3 requires.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.736 is well above the <=0.016 BP4 threshold, and the intermediate score supports neither PP3 nor BP4.	spliceai revel bayesdel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband-level data exist to establish an alternate molecular basis for disease.	clinvar
BP6	N/A	Not applicable: ClinVar has no record for this variant, so no expert-panel benign assertion exists to apply.	clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous variants, and this is a missense change.	generic_acmg_combination_rules

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