IDH2c.515G>TLikely pathogenic

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Variant interpretation report

IDH2 c.515G>T, p.(Arg172Met)

NM_002168.3:c.515G>T NP_002159.2:p.(Arg172Met) View identifiers

Classification

Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About IDH2

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 strong (pathogenic) · 2 moderate (pathogenic) · 1 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 26 Jun 2026 · version 7.0.0

Evidence considered

View criteria

Applied evidence criteria

PS3 (strong): 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.
PM1 (moderate): 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.
PM2 (moderate): 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%).
PP3 (supporting): 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.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 4 Benign evidence criteria: 0

Pathogenic criteria applied · 4

PS3Strong

PS3 · strong

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.

PM1Moderate

PM1 · moderate

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.

PM2Moderate

PM2 · moderate

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%).

PP3Supporting

PP3 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.030 maximum delta

Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.

Applied · PS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

62 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV57468971, n = 62 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

27 criteria with recorded statuses: 4 met · 4 not met · 14 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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').

Met · 4

PS3 StrongIDH2 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. Details ▾Hide ▴

Evidence considered

IDH2 R172M identified as gain-of-function mutant in pooled functional screen
Correlated with known activating IDH2 R172K allele
REVEL score 0.731 (damaging prediction)

Still missing

Evidence derived from pooled functional screen rather than dedicated variant-specific functional characterization
No dedicated in vitro enzymatic assay for R172M specifically in the reviewed literature

Sources

PMID:27147599 ↗revel

PM1 ModerateIDH2 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. Details ▾Hide ▴

Evidence considered

R172 is a statistically significant hotspot residue (Cancer Hotspots)
Critical active site residue interacting with isocitrate β-carboxyl
Recurrent somatic mutation (COSMIC n=62)
Known activating alleles cluster at this residue

Sources

PMID:20171147 ↗PMID:27147599 ↗

PM2 ModerateThis 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%). Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (exomes)
Absent from gnomAD v4.1
Absent from gnomAD-Canada v1.0

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PP3 SupportingREVEL 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. Details ▾Hide ▴

Evidence considered

REVEL 0.731 (damaging)
BayesDel 0.444 (borderline)
SpliceAI max delta 0.03 (no splice impact)

Sources

revelbayesdelspliceai ↗

Not met · 4 · evaluated, threshold not reached

BA1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada; allele frequency does not exceed the 1% BA1 threshold. Details ▾Hide ▴

Evidence considered

Absent from all population databases

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS1 Variant is absent from population databases; allele frequency does not exceed the 0.3% BS1 threshold. Details ▾Hide ▴

Evidence considered

Absent from all population databases

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS3 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. Details ▾Hide ▴

Evidence considered

IDH2 R172M demonstrates gain-of-function activity in functional screen
inconsistent with benign effect

Sources

PMID:27147599 ↗

BP4 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. Details ▾Hide ▴

Evidence considered

REVEL 0.731 (damaging
contradicts benign prediction)
BayesDel 0.444 (borderline
not independently benign)

Sources

revelbayesdelspliceai ↗

Not assessed · 14 · no assessment recorded

PS1 No evidence that this same amino acid change (p.Arg172Met) has been previously established as pathogenic via a different nucleotide change at this codon. Details ▾Hide ▴

Still missing

No ClinVar entries for a different nucleotide change resulting in p.Arg172Met

PS2 No de novo observation data available for this variant. Details ▾Hide ▴

Still missing

No de novo testing or trio data available

PS4 No case-control prevalence data comparing affected individuals to controls available. Details ▾Hide ▴

Still missing

No case-control or cohort prevalence data available

PM6 No de novo observation available; paternity and maternity not confirmed. Details ▾Hide ▴

Still missing

No de novo data available

PP1 No family segregation data available for this variant. Details ▾Hide ▴

Still missing

No cosegregation data in affected families

PP2 Insufficient constraint data to determine whether IDH2 has a low rate of benign missense variation. HCI prior score is not available for this gene. Details ▾Hide ▴

Still missing

No HCI prior or gene-level missense constraint metric available

PP4 No patient phenotype or family history information available to assess specificity for a disease with single genetic etiology. Details ▾Hide ▴

Still missing

No patient phenotype data provided

PP5 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. Details ▾Hide ▴

Still missing

No expert panel or reputable clinical source has classified this variant as pathogenic in germline context

BS2 No observation of this variant in healthy adult individuals available. Details ▾Hide ▴

Still missing

No healthy control observation data

BS4 No family segregation data available to evaluate lack of segregation in affected family members. Details ▾Hide ▴

Still missing

No family segregation data

BP2 No phase information available; no observation in trans or cis with a known pathogenic variant. Details ▾Hide ▴

Still missing

No phase data available

BP5 No observation of this variant in a case with an alternate molecular basis for disease. Details ▾Hide ▴

Still missing

No alternate molecular diagnosis data available

BP6 No reputable source has classified this variant as benign. The sole ClinVar submission classifies as 'risk factor' without assertion criteria. Details ▾Hide ▴

Still missing

No reputable benign classification available

PS5 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. Details ▾Hide ▴

Still missing

No expert panel or clinical testing laboratory has classified this variant as pathogenic in a germline context

Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AMissense 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). Details ▾Hide ▴

Evidence considered

Variant class is missense substitution
not a predicted null variant

Sources

pvs1_generic_framework ↗

PM5 N/ANo same-residue pathogenic missense comparator variants identified in ClinVar. Automated PM5 candidate harvesting could not confirm classic same-residue PM5 semantics. Details ▾Hide ▴

Still missing

Other pathogenic missense variants at R172 (R172K
R172S
R172G) are documented in somatic cancer literature but not captured as PM5 candidates in ClinVar

BP1 N/AIDH2 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. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies only to synonymous variants; this is a missense substitution (c.515G>T, p.Arg172Met). Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: IDH2
Transcript: NM_002168.3
Coding (HGVS c.): NM_002168.3:c.515G>T
Protein (HGVS p.): NP_002159.2:p.(Arg172Met)
GRCh38: chr15:90088606 C>A
GRCh37: chr15:90631838 C>A
ClinVar: 375986
COSMIC: COSV57468971

Gene diagram

Every interpreted variant in IDH2, mapped onto the exon structure of NM_002168.3. Select a row to find it on the plot.

IDH2NM_002168.3

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in IDH2 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -84 bp

0.030

SpliceAI acceptor gainat -168 bp

0.010

SpliceAI donor lossat +0 bp

0.000

SpliceAI donor gainat -19 bp

0.000

Pangolin splice lossmagnitude shown

-0.010

Pangolin splice gain

0.000

Other predictors

REVEL: 0.731
BayesDel: 0.444

How the predictions were used

Evidence considered

REVEL 0.731 (damaging)
BayesDel 0.444 (borderline)
SpliceAI max delta 0.03 (no splice impact)

Sources

revelbayesdelspliceai ↗

Evidence considered

REVEL 0.731 (damaging
contradicts benign prediction)
BayesDel 0.444 (borderline
not independently benign)

Sources

revelbayesdelspliceai ↗

BP7 N/ABP7 applies only to synonymous variants; this is a missense substitution (c.515G>T, p.Arg172Met). Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.731. BayesDel score = 0.443824.

2 paper records listed. 1 cited in the classification.

Cited in the classification

Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles.

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.
→ PS3 → PM1 Names this variant
PMID 27147599 ↗
Source detail

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

Other recorded publications

The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate.

Demonstrates that IDH2 R172K exhibits neomorphic enzymatic activity converting α-ketoglutarate to 2-hydroxyglutarate. The R172 residue is identified as a critical active site position analogous to IDH1 R132. IDH2 R172M (p.Arg172Met) was not examined or mentioned in this study.
Does not name this variant
PMID 20171147 ↗
Quoted passage
Mutation of IDH2 R172K enhances α-ketoglutarate-dependent NADPH consumption
Results throughout; Figures 1-3

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.030 Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

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

OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57468971, n = 62 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.