NM_002168.3:c.515G>T

IDH2 · NP_002159.2:p.(Arg172Met) · NM_002168.3

GRCh37: chr15:90631838 C>A · GRCh38: chr15:90088606 C>A

Gene: IDH2 Transcript: NM_002168.3

Final call

Likely Pathogenic

PS3 strong PM1 moderate PM2 moderate PP3 supporting

Variant details

Gene

IDH2

Transcript

NM_002168.3

Protein

NP_002159.2:p.(Arg172Met)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

IDH2 R172M has been identified as a gain-of-function mutant in a systematic functional interrogation screen (PMID:27147599), correlating with the known activating IDH2 R172K allele, satisfying PS3 at strong strength.

The variant affects IDH2 codon 172, a well-established mutational hotspot and critical active site residue that interacts with the β-carboxyl of isocitrate, satisfying PM1 at moderate strength.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, satisfying PM2 at moderate strength.

REVEL score of 0.731 predicts a deleterious effect, satisfying PP3 at supporting strength.

Applying generic ACMG/AMP 2015 final classification combination rules (PMID:25741868): 1 Strong (PS3) + 2 Moderate (PM1, PM2) + 1 Supporting (PP3) meets the Likely Pathogenic threshold ('1 Strong and 1-2 Moderate').

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Missense variant (p.Arg172Met); does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not assessed	No evidence that this same amino acid change (p.Arg172Met) has been previously established as pathogenic via a different nucleotide change at this codon.
PS2	Not assessed	No de novo observation data available for this variant.
PS3	Met	IDH2 R172M has been identified as a gain-of-function mutant in a systematic functional interrogation screen (PMID:27147599), correlating with the known activating IDH2 R172K allele. The neomorphic enzymatic activity converting α-ketoglutarate to 2-hydroxyglutarate is a well-established disease mechanism for IDH2 R172 codon variants. REVEL score of 0.731 supports a deleterious effect.	PMID:27147599 revel
PS4	Not assessed	No case-control prevalence data comparing affected individuals to controls available.
PS5	Not assessed	No reputable germline source has classified this variant as pathogenic. The sole ClinVar submission classifies as 'risk factor' without assertion criteria (SCV002047545). OncoKB 'Likely Oncogenic' classification is derived from somatic cancer context.
PM1	Met	IDH2 codon 172 (p.Arg172) is a well-established mutational hotspot in myeloid malignancies and gliomas. The arginine at position 172 is a critical active site residue that interacts with the β-carboxyl of isocitrate (PMID:20171147). Cancer Hotspots analysis confirms this residue is statistically significant. COSMIC reports this exact variant in 62 somatic cancer samples.	PMID:20171147 PMID:27147599
PM2	Met	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population databases, consistent with a rare pathogenic variant (allele frequency <0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue pathogenic missense comparator variants identified in ClinVar. Automated PM5 candidate harvesting could not confirm classic same-residue PM5 semantics.
PM6	Not assessed	No de novo observation available; paternity and maternity not confirmed.
PP1	Not assessed	No family segregation data available for this variant.
PP2	Not assessed	Insufficient constraint data to determine whether IDH2 has a low rate of benign missense variation. HCI prior score is not available for this gene.
PP3	Met	REVEL score of 0.731 predicts a deleterious effect. BayesDel score of 0.444 is borderline and does not independently support or contradict. SpliceAI predicts no splicing impact (max delta score 0.03), consistent with a missense variant acting through protein-level mechanisms.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history information available to assess specificity for a disease with single genetic etiology.
PP5	Not assessed	No reputable germline source has classified this variant as pathogenic. The single ClinVar submission (SCV002047545, 'risk factor') lacks assertion criteria. OncoKB 'Likely Oncogenic' is a somatic cancer resource, not a germline classification.
BA1	Not met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada; allele frequency does not exceed the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Variant is absent from population databases; allele frequency does not exceed the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No observation of this variant in healthy adult individuals available.
BS3	Not met	Functional evidence demonstrates gain-of-function activity for IDH2 R172M (PMID:27147599); this contradicts a benign functional effect. The variant is correlated with known activating IDH2 R172 mutations which exhibit neomorphic 2-hydroxyglutarate production.	PMID:27147599
BS4	Not assessed	No family segregation data available to evaluate lack of segregation in affected family members.
BP1	N/A	IDH2 disease mechanism is primarily mediated by missense gain-of-function variants (e.g., R172, R140 codon mutations), not truncating variants. BP1 applies only to genes where primarily truncating variants cause disease.
BP2	Not assessed	No phase information available; no observation in trans or cis with a known pathogenic variant.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution.
BP4	Not met	REVEL score of 0.731 predicts a damaging effect, contradicting the requirement for multiple lines of computational evidence suggesting no impact. BayesDel 0.444 is borderline and does not provide independent support for a benign interpretation.	revel bayesdel spliceai
BP5	Not assessed	No observation of this variant in a case with an alternate molecular basis for disease.
BP6	Not assessed	No reputable source has classified this variant as benign. The sole ClinVar submission classifies as 'risk factor' without assertion criteria.
BP7	N/A	BP7 applies only to synonymous variants; this is a missense substitution (c.515G>T, p.Arg172Met).

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.