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.1 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.2 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, satisfying PM2 at moderate strength.3 REVEL score of 0.731 predicts a deleterious effect, satisfying PP3 at supporting strength.4 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').5
IDH2
Final classification
Likely Pathogenic
IDH2 c.515G>T · p.Arg172Met
IDH2
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.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PM1 moderate, PM2 moderate, PP3 supporting; combination = 1 strong + 2 moderate + 1 supporting, which maps to Likely Pathogenic.
Classification rationale
PS3PM1PM2PP3
Likely Pathogenic
IDH2 c.515G>T
PS3 + PM1 + PM2 + PP3
→
Likely Pathogenic
4
revel
5
generic_acmg_combination_rules
Gene diagram
· NM_002168.3 · variants mapped to exon structure
IDH2
NM_002168.3
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 375986)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.731. BayesDel score = 0.443824.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57468971, n = 62 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 1 further PMID triaged but not cited — see Sources & References.
Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles.
Searched
R172MArg172Metc.515G>TIDH2 R172
Found
IDH2 R172M identified as a gain-of-function mutant in a pooled functional screen of 474 cancer-associated alleles. R172M correlated with the known activating mutant IDH2 R172K, confirming oncogenic activity.
Variant
✓ Names this variant — characterised directly
Applied to
→PM1 supports · met
→PS3 supports · met
Why
Variant-specific functional data confirmed gain-of-function activity; referenced in PS3 and PM1 assessments.
Specifically, we found that other known gain-of-function mutants IDH2 R172M, IDH1 R132C, IDH1 R132S, IDH1 R132H and IDH1 R132L were highly correlated to the known gain-of-function mutant IDH2 R172K
Location Results, Figure 3D · Context Pooled ORF-based functional screen; allele-specific correlation analysis · full text
Sources & reference links
Triaged references · 1 PMID not cited in assessment
20171147 ↗
The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate.
ONCOKB