0%
IDH2c.515G>AUncertain significance
Print report
Variant interpretation report

IDH2 c.515G>A, p.(Arg172Lys)

NM_002168.3:c.515G>A NP_002159.2:p.(Arg172Lys) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About IDH2

No gene-level summary was recorded for this case.

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
PS3Supporting
PS3 · supporting

Multiple independent functional studies demonstrate that IDH2 R172K produces a neomorphic gain-of-function enzymatic activity, converting α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2HG). This well-established functional effect has been confirmed across AML (Ward 2010, Paschka 2010), glioma (Jin 2011), and cholangiocarcinoma models (Saha 2014). Enasidenib, a selective IDH2-R172K inhibitor, produces clinical responses in R172K-mutated AML (Stein 2017). However, all functional evidence derives from somatic cancer models and was not designed to assess germline pathogenicity per ACMG/AMP standards, limiting strength assignment to supporting.

PM1Moderate
PM1 · moderate

This variant affects residue R172, located in the active site of IDH2 and a well-established mutational hotspot across multiple cancer types. Cancer Hotspots confirms this residue is statistically significant. COSMIC reports this exact variant 467 times. The R172 residue is the IDH2 analog of the IDH1 R132 hotspot and is one of only two recurrently mutated residues in IDH2 (R140 and R172), both in the enzymatic active site.

PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at extremely low frequency (AF = 6.19e-7; 1/1,614,246 alleles, 0 homozygotes). The highest subpopulation frequency is in Ashkenazi Jewish (AF = 3.38e-5; 1/29,606 alleles). These frequencies are well below the 0.1% PM2 threshold for non-VCEP assessment. The variant is also absent from gnomAD-Canada v1.0.

PP3Supporting
PP3 · supporting

REVEL score of 0.733 predicts a deleterious effect on protein function. SpliceAI predicts no significant splice impact (max delta = 0.03), which is neither supportive nor contradictory for a missense variant. BayesDel score of 0.432 falls below the typical pathogenicity threshold (0.5) and does not support a deleterious prediction. Multiple lines of in silico evidence provide partial support for a deleterious effect.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

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 supporting, PM1 moderate, PM2 supporting, PP3 supporting; combination = 1 moderate + 3 supporting, which maps to VUS.

02The sources

Evidence at a glance

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

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. ClinVar API review status: no assertion criteria provided.

Context only ClinVar ↗
Functional evidence
Statement recorded

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

Applied · PS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
467 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV57468734, n = 467 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.

26 criteria with recorded statuses: 4 met · 17 not met · 1 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PM1 (moderate): The c.515G>A (p.Arg172Lys) variant affects a well-established mutational hotspot at residue R172 in the IDH2 active site, confirmed by Cancer Hotspots and recurrently observed in COSMIC (n=467).

PM2 (supporting): This variant is extremely rare in population databases, absent from gnomAD v2.1 and gnomAD-Canada, with a single heterozygous observation in gnomAD v4.1 (AF = 6.19e-7; 1/1,614,246 alleles), well below the 0.1% threshold.

PS3 (supporting): Multiple independent functional studies across AML, glioma, and cholangiocarcinoma models confirm that IDH2 R172K confers a neomorphic gain-of-function producing the oncometabolite 2-hydroxyglutarate. Enasidenib, a selective IDH2-mutant inhibitor, produces clinical responses in R172K-mutated AML, confirming oncogenic dependency. However, all functional evidence derives from somatic cancer models, limiting strength to supporting in a germline context.

PP3 (supporting): REVEL score of 0.733 predicts a deleterious effect on protein function. BayesDel (0.432) does not independently support pathogenicity, but the REVEL prediction provides computational support.

Summary: One moderate criterion (PM1) and three supporting criteria (PM2, PS3, PP3) are met. No benign criteria are met. Under generic ACMG/AMP 2015 combination rules (PMID:25741868), this combination does not reach the threshold for Likely Pathogenic (requires 2 moderate OR 1 moderate + 2 supporting). The total evidence of PM1 + PM2 + PS3_supporting + PP3 falls short of a Likely Pathogenic classification. This variant is classified as a Variant of Uncertain Significance (VUS).

CAUTION: All pathogenic evidence derives from somatic cancer contexts. IDH2 R172K is a well-established somatic oncogenic driver mutation. Its role in germline disease, if any, is not well characterized. The germline disease context identified for IDH2 (MDS/MPN overlap syndromes, PMID:33275756) does not specifically implicate this variant. Clinicians should interpret this germline VUS classification with the understanding that this variant is oncogenic in somatic tissues.

Met · 4

PS3 SupportingMultiple independent functional studies demonstrate that IDH2 R172K produces a neomorphic gain-of-function enzymatic activity, converting α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2HG). This well-established functional effect has been confirmed across AML (Ward 2010, Paschka 2010), glioma (Jin 2011), and cholangiocarcinoma models (Saha 2014). Enasidenib, a selective IDH2-R172K inhibitor, produces clinical responses in R172K-mutated AML (Stein 2017). However, all functional evidence derives from somatic cancer models and was not designed to assess germline pathogenicity per ACMG/AMP standards, limiting strength assignment to supporting. Details ▾Hide ▴
Evidence considered
  • PMID:20171147: Neomorphic 2HG production confirmed by IDH2 R172K mutant enzyme assays.
  • PMID:21326614: 2HG production confirmed
  • dominant negative function excluded for IDH2 R172 mutations including R172K.
  • PMID:25043045: IDH2-R172K blocks hepatocyte differentiation via 2HG production in IHCC
  • most pronounced effect among IDH mutants tested.
  • PMID:20567020: IDH2 c.515G>A (p.R172K) recurrently identified in AML (n=22/805)
  • confirmed as somatic driver.
  • PMID:28588020: Enasidenib induces clinical responses in IDH2-R172K AML
  • confirming oncogenic dependency.
  • OncoKB: Curated oncogenicity label = Oncogenic.
Still missing
  • All functional evidence is from somatic cancer models
  • not germline-specific functional assays.
Sources
PMID:20171147 ↗PMID:21326614 ↗PMID:25043045 ↗PMID:20567020 ↗PMID:28588020 ↗oncokb ↗
PM1 ModerateThis variant affects residue R172, located in the active site of IDH2 and a well-established mutational hotspot across multiple cancer types. Cancer Hotspots confirms this residue is statistically significant. COSMIC reports this exact variant 467 times. The R172 residue is the IDH2 analog of the IDH1 R132 hotspot and is one of only two recurrently mutated residues in IDH2 (R140 and R172), both in the enzymatic active site. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: Residue R172 is a statistically significant hotspot (not a formal source_registry key).
  • COSMIC COSV57468734: 467 somatic observations of this exact variant.
  • Residue R172 is in the IDH2 active site
  • analogous to IDH1 R132 hotspot.
Sources
PMID:20171147 ↗PMID:20567020 ↗
PM2 SupportingThis variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at extremely low frequency (AF = 6.19e-7; 1/1,614,246 alleles, 0 homozygotes). The highest subpopulation frequency is in Ashkenazi Jewish (AF = 3.38e-5; 1/29,606 alleles). These frequencies are well below the 0.1% PM2 threshold for non-VCEP assessment. The variant is also absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: Absent.
  • gnomAD v4.1: AF = 6.19e-7 (1/1
  • 614
  • 246 alleles
  • 0 homozygotes).
  • gnomAD-Canada v1.0: Absent.
  • Maximum subpopulation AF = 3.38e-5 (Ashkenazi Jewish)
  • well below 0.1% threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 SupportingREVEL score of 0.733 predicts a deleterious effect on protein function. SpliceAI predicts no significant splice impact (max delta = 0.03), which is neither supportive nor contradictory for a missense variant. BayesDel score of 0.432 falls below the typical pathogenicity threshold (0.5) and does not support a deleterious prediction. Multiple lines of in silico evidence provide partial support for a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.733 (above 0.5 threshold
  • supports deleterious).
  • BayesDel: 0.432 (below 0.5 threshold
  • does not support deleterious).
  • SpliceAI: max delta 0.03 (no splicing impact predicted).
Still missing
  • BayesDel does not support PP3
  • REVEL alone is a single predictor line of evidence.
Sources
revelbayesdelspliceai ↗

Not met · 17 · evaluated, threshold not reached

PS1 No alternative nucleotide change at codon 172 (AGA) producing the same p.Arg172Lys substitution has been established as pathogenic. The reference codon AGA at positions c.514-516 can only produce p.Arg172Lys via c.515G>A; no independent nucleotide path to the same amino acid change exists in this reference context. Details ▾Hide ▴
Evidence considered
  • Single nucleotide path from AGA to AAA via c.515G>A
  • no alternative nucleotide change producing Arg172Lys is possible at this codon.
PS2 No de novo occurrence data available for this variant. No reports of confirmed or unconfirmed de novo observation were identified in ClinVar submissions, literature, or any other source. Details ▾Hide ▴
Evidence considered
  • No de novo data identified in any source.
Still missing
  • No de novo testing or reporting identified.
PS4 No case-control data demonstrating statistically significant enrichment of this variant in affected individuals versus controls in a germline context. The variant is recurrent in somatic cancers (COSMIC n=467), but somatic prevalence does not satisfy PS4 for germline ACMG/AMP assessment. Details ▾Hide ▴
Evidence considered
  • COSMIC COSV57468734: 467 somatic observations across multiple cancer types. No germline case-control data available.
Still missing
  • No germline case-control or cohort enrichment data.
PM6 No de novo observation data available for this variant, with or without confirmed parentage. No reports of de novo occurrence were identified in ClinVar, literature, or any other source. Details ▾Hide ▴
Evidence considered
  • No de novo data identified.
Still missing
  • No de novo testing or reporting identified.
PP1 No co-segregation data available for this variant. No family studies or pedigree analyses were identified in any source. Details ▾Hide ▴
Evidence considered
  • No co-segregation data identified.
Still missing
  • No family studies or segregation analysis available.
PP4 No specific phenotype or family history data are available for this variant in a germline context. While the variant is associated with multiple cancer types somatically (AML, glioma, IHCC), no germline phenotype specificity data exist. Details ▾Hide ▴
Evidence considered
  • No germline phenotype or family history data available.
Still missing
  • No germline phenotype data.
PP5 ClinVar lists this variant as 'risk factor' from a single submitter with no assertion criteria provided (trust_tier=weak_noisy). PMID:22918138 flagged for PP5 is an Association for Molecular Pathology guideline paper on clinical diagnostic genome sequencing that does not mention this specific variant. No reputable germline source has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar VariationID 375987: 'risk factor'
  • single submitter
  • no assertion criteria
  • no valid PMIDs.
  • PMID:22918138: General AMP guideline paper
  • variant not mentioned.
Still missing
  • No expert panel or reputable clinical laboratory germline classification.
Sources
clinvar ↗
BA1 The overall allele frequency is 6.19e-7 (0.00006%), far below the 1% BA1 threshold. This variant is not a common polymorphism. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 6.19e-7
  • well below 1% BA1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 The overall allele frequency is 6.19e-7 (0.00006%), far below the 0.3% BS1 threshold for non-VCEP assessment. The highest subpopulation frequency (Ashkenazi Jewish, 3.38e-5) is also well below 0.3%. This variant is not observed at a frequency consistent with benign variation. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 6.19e-7
  • max subpop AF = 3.38e-5 (Ashkenazi Jewish). All well below 0.3% BS1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No data demonstrating observation of this variant in healthy adult controls at a frequency consistent with benign variation. The single gnomAD v4.1 observation lacks phenotypic annotation and does not constitute BS2-level evidence. Details ▾Hide ▴
Evidence considered
  • No healthy control cohort data available. Single gnomAD observation lacks phenotype confirmation.
Still missing
  • No healthy adult control data with phenotypic confirmation.
BS3 Well-established functional studies demonstrate that IDH2 R172K has a neomorphic gain-of-function effect (2-hydroxyglutarate production) rather than a benign or neutral effect on protein function. The functional evidence supports a damaging, not benign, interpretation. Details ▾Hide ▴
Evidence considered
  • Multiple studies confirm neomorphic 2HG production
  • not benign function.
  • Functional evidence is contrary to BS3 application.
Sources
PMID:20171147 ↗PMID:21326614 ↗PMID:25043045 ↗
BS4 No non-segregation data available. No family studies demonstrating absence of co-segregation with disease were identified. Details ▾Hide ▴
Evidence considered
  • No non-segregation data identified.
Still missing
  • No family studies available.
BP2 No data on observation of this variant in trans with a known pathogenic variant. No phase information is available for the single gnomAD observation. Details ▾Hide ▴
Evidence considered
  • No phase or trans configuration data available.
Still missing
  • No phase information for the single gnomAD allele.
BP4 REVEL score of 0.733 predicts a deleterious effect, not a benign one. BayesDel 0.432 is borderline. SpliceAI (max delta 0.03) predicts no splicing impact, which is neutral. Multiple lines of computational evidence do not support a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL 0.733 supports deleterious
  • not benign
  • prediction.
  • BayesDel 0.432 is borderline
  • does not clearly support benign.
  • SpliceAI 0.03 indicates no splicing impact (neutral).
Sources
revelbayesdelspliceai ↗
BP5 No alternative molecular basis for disease has been identified in individuals harboring this variant. No data suggesting another causative variant explains the phenotype in carriers. Details ▾Hide ▴
Evidence considered
  • No alternative molecular basis data available.
Still missing
  • No data on alternative molecular diagnoses in carriers.
BP6 This variant has not been reported as benign or likely benign by any reputable source. ClinVar lists it as 'risk factor' (not benign). No expert panel or clinical testing laboratory has classified this variant as benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: 'risk factor'
  • not benign. No benign classification from any source.
Sources
clinvar ↗
PS5 ClinVar lists this variant as 'risk factor' (VariationID: 375987) from a single submitter (Clinical Pathology, Tanta University) with no assertion criteria provided and no valid supporting PMIDs. The single submission uses case-control methodology but lacks ACMG criteria. OncoKB classifies as 'Oncogenic' but this is a somatic cancer knowledgebase, not a germline classification. No reputable germline source has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar: Single submission
  • 'risk factor'
  • no assertion criteria provided
  • no valid PMIDs
  • trust_tier=weak_noisy.
  • OncoKB: Oncogenic (somatic context).
Still missing
  • No expert panel or clinical testing laboratory germline classification available.
Sources
clinvar ↗oncokb ↗

Not assessed · 1 · no assessment recorded

PP2 HCI prior not available for IDH2 (gene_not_supported). Without gene-level missense constraint metrics or an established low rate of benign missense variation, PP2 cannot be reliably assessed. While IDH2 is an oncogene where missense mutations at specific hotspots drive disease, the gene-level constraint data needed for formal PP2 application are absent. Details ▾Hide ▴
Evidence considered
  • HCI prior: not found (gene_not_supported). No gene-level missense constraint scores available.
Still missing
  • No HCI prior or gene-level missense constraint data available for IDH2.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.515G>A, p.Arg172Lys). It 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
  • Missense substitution
  • variant_bucket=other
  • canonical_splice_consensus=false
  • apply_generic_pvs1_framework=false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM5 N/AAutomated candidate harvesting did not identify any qualifying comparator variant at residue R172 with a different amino acid change and established pathogenicity. No same-residue pathogenic missense with a different alteration was found in ClinVar or other sources. Details ▾Hide ▴
Evidence considered
  • pm5_candidates summary: total_candidates_seen=0
  • same_residue_candidates=0
  • recommendation=not_applicable.
Sources
pm5_candidates
BP1 N/AIDH2-associated disease, to the extent a germline mechanism exists, involves gain-of-function missense mutations (R140, R172) rather than a truncating-only mechanism. BP1 applies specifically to genes where only truncating variants cause disease, which is not the case for IDH2. Details ▾Hide ▴
Evidence considered
  • IDH2 disease mechanism involves missense gain-of-function
  • not truncating-only.
BP7 N/AThis is a missense variant (c.515G>A, p.Arg172Lys), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splicing impact. While SpliceAI predicts no significant splice impact (max delta 0.03), BP7 is structurally inapplicable to missense variants. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 applies only to synonymous/intronic variants.

Identifiers

Gene
IDH2
Transcript
NM_002168.3
Coding (HGVS c.)
NM_002168.3:c.515G>A
Protein (HGVS p.)
NP_002159.2:p.(Arg172Lys)
GRCh38
chr15:90088606 C>T
GRCh37
chr15:90631838 C>T
ClinVar
375987
COSMIC
COSV57468734

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…
gnomAD v4.1 1 / 1,614,246 alleles AF 6.19e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,614,246 alleles · 0 hom
Ashkenazi Jewish1 / 29,606 3.4e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, African/African American, European (non-Finnish).

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19484e-07; MAF= 0.00006%, 1/1614246 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37769e-05; MAF= 0.00338%, 1/29606 alleles, homozygotes = 0).

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 +4 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.010

Other predictors

REVEL
0.733
BayesDel
0.432

How the predictions were used

PP3 SupportingREVEL score of 0.733 predicts a deleterious effect on protein function. SpliceAI predicts no significant splice impact (max delta = 0.03), which is neither supportive nor contradictory for a missense variant. BayesDel score of 0.432 falls below the typical pathogenicity threshold (0.5) and does not support a deleterious prediction. Multiple lines of in silico evidence provide partial support for a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.733 (above 0.5 threshold
  • supports deleterious).
  • BayesDel: 0.432 (below 0.5 threshold
  • does not support deleterious).
  • SpliceAI: max delta 0.03 (no splicing impact predicted).
Still missing
  • BayesDel does not support PP3
  • REVEL alone is a single predictor line of evidence.
Sources
revelbayesdelspliceai ↗
BP4 REVEL score of 0.733 predicts a deleterious effect, not a benign one. BayesDel 0.432 is borderline. SpliceAI (max delta 0.03) predicts no splicing impact, which is neutral. Multiple lines of computational evidence do not support a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL 0.733 supports deleterious
  • not benign
  • prediction.
  • BayesDel 0.432 is borderline
  • does not clearly support benign.
  • SpliceAI 0.03 indicates no splicing impact (neutral).
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.515G>A, p.Arg172Lys), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splicing impact. While SpliceAI predicts no significant splice impact (max delta 0.03), BP7 is structurally inapplicable to missense variants. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 applies only to synonymous/intronic variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.733. BayesDel score = 0.431707.

7 paper records listed. 5 cited in the classification.

Cited in the classification

  • The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate.
    Ward PS et al. · 2010 Mar 16
    IDH2 R172K confirmed to have neomorphic enzyme activity converting α-ketoglutarate to the oncometabolite 2-hydroxyglutarate. Tumor 2HG was elevated in AML patients harboring IDH2 R172 mutations. All reported IDH1 and IDH2 mutations were heterozygous with retention of one wild-type allele, arguing against simple loss of function.
    → PS3 → PM1 Names this variant
    PMID 20171147 ↗
    Source detail
    The IDH2 mutations which have been identified in gliomas occur at the analogous residue to IDH1 R132, IDH2 R172.

    Location Introduction, paragraph 1; Results, paragraphs 2-4; Figure 1-2

    Context Enzymatic assays for α-KG to 2HG conversion using recombinant IDH2 R172K mutant protein; 2HG measurement in AML patient samples

  • IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication.
    IDH2 c.G515A (c.515G>A, p.R172K) was identified in 22 of 805 AML patients (2.7%). IDH2 R172K mutations were mutually exclusive with FLT3-ITD and associated with adverse prognosis in CN-AML with mutated NPM1 without FLT3-ITD (5-year OS 41% vs 65%).
    → PS3 → PM1 Names this variant
    PMID 20567020 ↗
    Source detail
    All IDH2 mutations were missense mutations, either c.G419A or c.G515A, predicted to cause amino acid changes p.R140Q (n=48) and p.R172K (n=22), respectively.

    Location Table 1; Results, paragraphs 1-2; Survival Analysis section

    Context DHPLC and direct sequencing of exon 4 of IDH1/IDH2 in 805 AML patients enrolled on AMLSG treatment trials; survival analysis with median 6.3-year follow-up

  • 2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations.
    Jin G et al. · 2011 Feb 4
    IDH2 R172K, along with R172M and R172G, produces 2-hydroxyglutarate in glioma models. The study excluded a dominant negative mechanism, confirming that the shared gain-of-function (2HG production), not dominant negative inhibition, is the oncogenic mechanism of IDH2 R172 mutations.
    → PS3 Names this variant
    PMID 21326614 ↗
    Source detail
    R172K, R172M, and R172G are the IDH2 substitutions observed in gliomas.

    Location Introduction, paragraph 1

    Context NADP+-dependent IDH enzyme activity assays; 2HG production quantification; WT:mutant heterodimer studies

  • Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer.
    Saha SK et al. · 2014 Sep 4
    IDH2-R172K expressed in mouse hepatoblasts produced increased 2HG and blocked hepatocyte differentiation, with IDH2-R172K causing the most pronounced effects among IDH mutants tested. Treatment with a mutant IDH inhibitor attenuated 2HG production and restored differentiation.
    → PS3 Names this variant
    PMID 25043045 ↗
    Source detail
    HBs expressing mutant IDH1 (R132C, R132H) or IDH2 (R140Q, R172K) produced increased 2HG, but exhibited morphology and proliferation rates indistinguishable from vector and IDH wild type (WT) controls.

    Location Results, paragraph 1; Extended Data Figure 1

    Context Mouse hepatoblast differentiation assay; 2HG quantification; IDH mutant inhibitor (ML309) treatment

  • Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia.
    Enasidenib, a first-in-class selective inhibitor of mutant IDH2, demonstrated clinical efficacy in IDH2-R172K-mutated relapsed/refractory AML. At 100 mg daily, enasidenib reduced plasma 2-HG by a median of 28% and maximum of 94% in patients with IDH2-R172K mutations. Overall response rate was 53.3% for IDH2-R172 patients.
    → PS3 Names this variant
    PMID 28588020 ↗
    Source detail
    enasidenib 100 mg daily reduced plasma 2-HG levels from baseline by a median and maximum of 93% and 99%, respectively, in patients with IDH2-R140Q mutations and by 28% and 94% in patients with IDH2-R172K mutations

    Location Results, Pharmacokinetics/Pharmacodynamics subsection; Efficacy subsection

    Context Phase 1/2 clinical trial (NCT01915498); 239 patients with mutant-IDH2 advanced myeloid malignancies; dose-escalation and expansion cohorts

Other recorded publications

  • AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations.
    No paper-specific finding is recorded.
    PMID 28193778 ↗
  • The 2021 WHO Classification of Tumors of the Central Nervous System: a summary.
    Louis DN et al. · 2021
    No paper-specific finding is recorded.
    PMID 34185076 ↗

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

gnomAD v4.1 1 / 1,614,246 recorded alleles 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 ↗

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Statements for reports

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

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19484e-07; MAF= 0.00006%, 1/1614246 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37769e-05; MAF= 0.00338%, 1/29606 alleles, homozygotes = 0).

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 = 375987)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.733. BayesDel score = 0.431707.

Functional

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

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57468734, n = 467 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.