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 PP3 moderate

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): absent from all population databases — gnomAD v2.1 exomes, v4.1 exomes, and gnomAD-Canada v1.0 genomes (observed AF = 0).

PP3 (Moderate): REVEL 0.736 falls within the ClinGen SVI-calibrated moderate band (0.644–0.773).

Overall: VUS — the 1 moderate + 1 supporting combination satisfies no Pathogenic, Likely Pathogenic, Benign, or Likely Benign threshold in the generic ACMG/AMP 2015 rules.

Final determination: Generic ACMG/AMP 2015 combination rules (PMID:25741868): with only PM2 (supporting) and PP3 (moderate) met - 1 moderate + 1 supporting - none of the Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination thresholds is satisfied, 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	N/A	Not applicable: this is a missense substitution (p.Thr138Asn), so no null-variant mechanism such as nonsense-mediated decay applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no established pathogenic variant producing the same amino-acid change (p.Thr138Asn) exists; this is the only single-nucleotide change that yields Asn at codon 138.	clinvar pm5_candidates
PS2	Not assessed	Not assessed: no proband, parental, or de novo occurrence data were available to evaluate.
PS3	Not assessed	Not assessed: no validated variant-specific functional assay data were available; in silico predictions do not qualify as functional studies.	generic_acmg_combination_rules oncokb spliceai clinvar
PS4	Not assessed	Not assessed: no case-control or cohort enrichment data exist for this variant.	clinvar generic_acmg_combination_rules
PM1	Not assessed	Not assessed: position 138 is not a known IDH2 hotspot (R140/R172 are), and no protein-domain annotation was available to evaluate the critical-domain arm.
PM2	Met	Met (supporting): absent from all population databases — gnomAD v2.1 exomes, v4.1 exomes, and gnomAD-Canada v1.0 genomes (observed AF = 0).	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no second pathogenic allele or phase (trans/cis) information was available, and no recessive germline disorder applies.	clinvar generic_acmg_combination_rules
PM4	N/A	Not applicable: missense substitution produces no change in protein length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense change at residue 138 has been established as pathogenic.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no de novo occurrence data, confirmed or unconfirmed, were available.
PP1	Not assessed	Not assessed: no segregation or pedigree data were available, and IDH2's germline disease association is not established.
PP2	Not assessed	Not assessed: missense is a common disease mechanism for IDH2, but no gene-level missense constraint metric was available.	oncokb
PP3	Met	Met (moderate): REVEL 0.736 falls within the ClinGen SVI-calibrated PP3 moderate band (0.644–0.773).	revel spliceai bayesdel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family-history data were available to evaluate.	clinvar generic_acmg_combination_rules
PP5	Not met	Not met: this variant is absent from ClinVar, so no expert-panel pathogenic classification exists to apply.	clinvar generic_acmg_combination_rules
BA1	Not met	Not met: allele frequency is 0 in all population datasets, far below the >5% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: allele frequency 0 cannot exceed the expected frequency for an ultra-rare IDH2 germline disorder.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: no carriers or homozygotes were observed in any consulted cohort.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional study data were available to demonstrate absence of a damaging effect.	generic_acmg_combination_rules oncokb spliceai clinvar
BS4	Not assessed	Not assessed: no family testing data were available to evaluate non-segregation.
BP1	Not met	Not met: IDH2 disease is mediated by missense variants, so the truncating-only mechanism does not apply.	oncokb pvs1_variant_assessment
BP2	Not assessed	Not assessed: no trans or cis co-occurrence with a second variant was observed.	clinvar generic_acmg_combination_rules
BP3	N/A	Not applicable: this is a missense substitution, not an in-frame insertion/deletion in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.736 is far above the ClinGen-calibrated BP4 supporting threshold (≤0.016).	revel spliceai bayesdel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband-level data were available to identify an alternative molecular basis.	clinvar generic_acmg_combination_rules
BP6	Not met	Not met: this variant is absent from ClinVar, so no expert-panel benign classification exists to apply.	clinvar generic_acmg_combination_rules
BP7	N/A	Not applicable: this is a missense substitution, not a synonymous variant, so the silent-variant premise does not hold.	generic_acmg_combination_rules

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