Variant classification summary

NM_002168.4:c.419G>A

IDH2 · NP_002159.2:p.(Arg140Gln) · NM_002168.4

GRCh37: chr15:90631934 C>T · GRCh38: chr15:90088702 C>T

Gene: IDH2 Transcript: NM_002168.4

Final call

Pathogenic

PS1 strong PS3 strong PM2 supporting PP3 moderate

Variant details

Gene

IDH2

Transcript

NM_002168.4

Protein

NP_002159.2:p.(Arg140Gln)

gnomAD AF

4.3996847099182524e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS1 strong supports the exact previously established p.Arg140Gln change.

2

Pathogenic: PS3 strong shows reduced normal IDH2 activity and increased neomorphic 2-hydroxyglutarate production.

3

Pathogenic: PM2 supporting is supported by gnomAD v4.1 allele frequency 4.39968e-05 with zero homozygotes.

4

Pathogenic: PP3 moderate is supported by REVEL 0.891, above the 0.773 moderate threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria (PS1 and PS3) satisfy the Pathogenic combination rule; the additional PM2 and PP3 evidence is concordant.

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: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Met	Met, p.Arg140Gln is the exact amino-acid change reported in disease cohorts and has 7 Pathogenic and 5 Likely pathogenic ClinVar laboratory submissions.	clinvar PMID:20567020 PMID:21889589 PMID:21647154
PS2	Not assessed	Not assessed: ClinVar reports de novo status with trio-confirmed parental status, but disease phenotype and absence of family history are undocumented.	clinvar
PS3	Met	Met, strong: recombinant assays showed a 60% normal-activity reduction, while patient-derived cells produced 14.4 versus 1.8 nmol per hour per mg protein in controls.	PMID:21647154 PMID:21889589
PS4	Not met	Not met: variant-bearing affected cohorts were reported, but no qualifying case-control OR/RR with a 95% CI excluding 1.0 was available.	PMID:20171147 PMID:20567020 PMID:20692206 PMID:21647154
PM1	Not assessed	Not assessed: a reported R140 hotspot lacks an allowed VCEP hotspot route, and no auditable IDH2 domain-plus-benign-variation evidence is available.
PM2	Met	Met at supporting strength: gnomAD v4.1 shows AF=4.39968e-05, below the supplied PM2 cutoff of 0.0001, with zero homozygotes.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: affected type II observations were heterozygous IDH2 p.Arg140Gln, with no evidence of a recessive pathogenic variant in trans.	PMID:21889589
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: R140W and R140G are reported alternate changes, but neither is established as pathogenic in the supplied evidence.	PMID:21647154 PMID:21889589 pm5_candidates
PM6	Not met	Not met: the available de novo report states parental status was confirmed by trio analysis, not unconfirmed assumed de novo status.	clinvar
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or family segregation data are documented for this variant.
PP2	Not assessed	Not assessed: the supplied evidence lacks gene-level proof of both low benign missense variation and a common missense disease mechanism for IDH2.
PP3	Met	Met at moderate strength: REVEL 0.891 exceeds the PP3 moderate threshold of 0.773 but is below the strong threshold of 0.932.	revel
PP4	Not assessed	Not assessed: the case materials provide no patient phenotype or family history to evaluate specificity for a single-gene disease.
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel pathogenic classification; its available assertions are non-expert submissions.	clinvar
BA1	Not met	Not met: the highest reported allele frequency is 0.00120, well below the 0.05 BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the highest observed frequency is 0.00120, below the 0.01 default, without a disorder-specific maximum-credible-frequency calculation.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: gnomAD reports 71 alleles but does not establish a specific healthy adult heterozygote with fully penetrant early-onset disease expectations.	gnomad_v4 gnomad_v2
BS3	Not met	Not met: exact-variant assays showed reduced normal activity and approximately eightfold increased neomorphic activity, not an absence of damaging effect.	PMID:21647154 PMID:21889589
BS4	Not assessed	Not assessed: no affected relatives tested negative for the variant, and no family-based non-segregation analysis is documented.
BP1	Not assessed	Not assessed: recurrent IDH2 missense reports do not establish whether disease is primarily caused by truncating variants.
BP2	Not assessed	Not assessed: the available heterozygous observations provide no second pathogenic variant or cis/trans phase information for BP2.	PMID:21889589
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.891 is above the BP4 supporting cutoff of 0.29, so it does not support a tolerated missense effect.	revel
BP5	Not assessed	Not assessed: no case was documented in which the variant co-occurred with an alternate molecular basis for disease.
BP6	Not met	Not met: ClinVar provides no exact-variant expert-panel benign classification, and available submissions are pathogenic or likely pathogenic.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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