About IDH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
IDH1 c.394C>T, p.(Arg132Cys)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 5
Benign evidence criteria: 0
Pathogenic criteria applied · 5
PS3Strong
PS3 · strong
Functional studies demonstrate that the IDH1 R132C variant confers a neomorphic gain-of-function activity, producing the oncometabolite 2-hydroxyglutarate (2-HG). PMID:23954893 directly tested R132C in a mouse bone marrow transplantation model, showing accelerated leukemogenesis with shortened survival (median 83 vs 167 days, p<0.001). PMID:19935646 established the mechanism that R132 mutations (including R132H) produce 2-HG. PMID:29670690 confirmed R132C as a target of the FDA-approved inhibitor ivosidenib (AG-120) with nanomolar IC50 (enzyme 13 nM, cellular 8 nM), providing orthogonal pharmacologic validation of the variant's functional significance.
PM1Moderate
PM1 · moderate
Residue R132 lies within the active site of IDH1 (residues 104-136), a well-established critical functional domain. R132 is the single most recurrently mutated amino acid in IDH1 across all cancer types and is flagged as a statistically significant hotspot by cancerhotspots.org. PMID:19935646 demonstrates that mutations at R132 abrogate normal isocitrate-to-αKG conversion and confer neomorphic 2-HG production.
PM2Moderate
PM2 · moderate
Absent from gnomAD v2.1 (0/251,292 alleles, AF=0.00%) and nearly absent from gnomAD v4.1 (1/1,613,126 alleles, AF=0.00006%). Both are well below the 0.1% PM2 threshold for a rare variant absent from population controls.
PM5Moderate
PM5 · moderate
Multiple different missense changes at the same amino acid residue R132 are established as pathogenic: R132H (c.395G>A, the most common IDH1 mutation in gliomas and AML), R132S (c.394C>A), R132G (c.394C>G), and R132L (c.395G>T). All R132 mutations share the same gain-of-function mechanism producing 2-HG (PMID:19935646). The current variant R132C (c.394C>T) occurs at the same critical residue, satisfying PM5.
PP3Supporting
PP3 · supporting
Multiple in silico tools predict a deleterious effect. REVEL score of 0.814 exceeds the 0.5 threshold for a damaging prediction. SpliceAI max delta score of 0.51 suggests possible splice-altering potential. BayesDel score of 0.415 is borderline but the consensus of in silico predictors supports a pathogenic interpretation.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: 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, PM5 moderate, PP3 supporting; combination = 1 strong + 3 moderate + 1 supporting, which maps to 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
1 / 1,613,126 alleles
gnomAD v4.1: 1 / 1,613,126 alleles. Recorded AF 6.19914e-07. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251292 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16256 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.510 maximum delta
Recorded SpliceAI maximum delta score: 0.510. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
10 reported laboratory submissions
8 Pathogenic · 1 pathogenic · 1 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
1377 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV61615256, n = 1377 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 5 met · 18 not met · 0 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
IDH1 c.394C>T (p.Arg132Cys) is a missense variant at the critical active-site residue R132, the most recurrently mutated amino acid in IDH1 across all cancer types.
Functional studies directly testing R132C demonstrate a neomorphic gain-of-function: the variant enzyme produces the oncometabolite 2-hydroxyglutarate and promotes leukemogenesis in a mouse transplantation model, with median survival shortened from 167 to 83 days (p<0.001).
R132C is effectively targeted by the FDA-approved mutant IDH1 inhibitor ivosidenib (AG-120) with nanomolar potency (IC50 13 nM enzyme, 8 nM cellular), and ivosidenib induces differentiation of primary R132C AML blasts ex vivo.
Multiple different missense changes at the same residue (R132H, R132S, R132G, R132L) are established as pathogenic and share the same gain-of-function mechanism, satisfying PM5.
The variant is essentially absent from population databases (gnomAD v2.1: 0/251,292 alleles; gnomAD v4.1: 1/1,613,126 alleles, AF=0.00006%), meeting PM2 for rarity in controls.
In silico predictors support a deleterious effect (REVEL 0.814) and possible splice alteration (SpliceAI max delta 0.51), contributing supporting evidence (PP3).
The variant has been reported in ClinVar as Pathogenic by multiple clinical laboratories and is recorded in COSMIC with 1,377 somatic observations.
Applying generic ACMG/AMP 2015 combination rules: PS3 (strong) + PM1 (moderate) + PM2 (moderate) + PM5 (moderate) + PP3 (supporting) → Pathogenic (class 5).
No criteria match.
Met · 5
PS3 StrongFunctional studies demonstrate that the IDH1 R132C variant confers a neomorphic gain-of-function activity, producing the oncometabolite 2-hydroxyglutarate (2-HG). PMID:23954893 directly tested R132C in a mouse bone marrow transplantation model, showing accelerated leukemogenesis with shortened survival (median 83 vs 167 days, p<0.001). PMID:19935646 established the mechanism that R132 mutations (including R132H) produce 2-HG. PMID:29670690 confirmed R132C as a target of the FDA-approved inhibitor ivosidenib (AG-120) with nanomolar IC50 (enzyme 13 nM, cellular 8 nM), providing orthogonal pharmacologic validation of the variant's functional significance. Details ▾Hide ▴
Evidence considered
- PMID:23954893: R132C cDNA from MDS patient directly tested in mouse transplantation assay
- cooperates with HoxA9 to accelerate leukemogenesis (median survival 83 days vs 167 days).
- PMID:19935646: R132 mutations produce the oncometabolite 2-hydroxyglutarate
- establishing gain-of-function neomorphic mechanism.
- PMID:29670690: AG-120 (ivosidenib) inhibits R132C enzyme with IC50 13 nM and R132C-expressing HT1080 cells with IC50 8 nM
- induces differentiation of primary R132C AML blasts.
Sources
PM1 ModerateResidue R132 lies within the active site of IDH1 (residues 104-136), a well-established critical functional domain. R132 is the single most recurrently mutated amino acid in IDH1 across all cancer types and is flagged as a statistically significant hotspot by cancerhotspots.org. PMID:19935646 demonstrates that mutations at R132 abrogate normal isocitrate-to-αKG conversion and confer neomorphic 2-HG production. Details ▾Hide ▴
Evidence considered
- R132 is in the IDH1 active site (isocitrate binding pocket)
- a critical functional domain.
- Statistically significant hotspot per cancerhotspots.org.
- PMID:19935646: R132 mutations disrupt catalytic activity and produce 2-HG.
Sources
PM2 ModerateAbsent from gnomAD v2.1 (0/251,292 alleles, AF=0.00%) and nearly absent from gnomAD v4.1 (1/1,613,126 alleles, AF=0.00006%). Both are well below the 0.1% PM2 threshold for a rare variant absent from population controls. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0/251
- 292 alleles (0.00%).
- gnomAD v4.1: 1/1
- 613
- 126 alleles (0.00006%).
Sources
PM5 ModerateMultiple different missense changes at the same amino acid residue R132 are established as pathogenic: R132H (c.395G>A, the most common IDH1 mutation in gliomas and AML), R132S (c.394C>A), R132G (c.394C>G), and R132L (c.395G>T). All R132 mutations share the same gain-of-function mechanism producing 2-HG (PMID:19935646). The current variant R132C (c.394C>T) occurs at the same critical residue, satisfying PM5. Details ▾Hide ▴
Evidence considered
- PMID:19935646: Multiple R132 missense mutations (R132H
- R132S
- R132C) share the 2-HG-producing gain-of-function mechanism.
- R132H (c.395G>A) is the canonical IDH1 pathogenic variant in gliomas and AML.
- PMID:29670690: AG-120 inhibits R132H
- R132C
- R132G
- R132L
- and R132S with comparable nanomolar potency.
Sources
PP3 SupportingMultiple in silico tools predict a deleterious effect. REVEL score of 0.814 exceeds the 0.5 threshold for a damaging prediction. SpliceAI max delta score of 0.51 suggests possible splice-altering potential. BayesDel score of 0.415 is borderline but the consensus of in silico predictors supports a pathogenic interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.814 (damaging).
- SpliceAI max delta: 0.51 (possible splice impact).
- BayesDel: 0.415 (borderline).
Sources
Not met · 18 · evaluated, threshold not reached
PS2 No de novo germline occurrence reported in the available literature. The variant is predominantly observed in somatic contexts (COSMIC n=1377) and as somatic mosaic in Ollier disease/Maffucci syndrome; no confirmed germline de novo report identified. Details ▾Hide ▴
Evidence considered
- No de novo germline report found. Variant is predominantly somatic.
Still missing
- De novo germline occurrence not investigated due to somatic predominance of this variant.
PS4 No case-control prevalence data available in a germline context. The variant has been extensively reported in somatic malignancies (COSMIC n=1377) but these represent somatic rather than germline observations. The ClinVar submissions classified as germline (n=3) lack controlled prevalence comparisons. Details ▾Hide ▴
Evidence considered
- COSMIC: n=1377 somatic observations. No germline case-control prevalence data.
Still missing
- Germline case-control prevalence data not available
- variant is overwhelmingly somatic.
Sources
PM6 No confirmed de novo germline observation reported in the available literature. The variant is predominantly observed in somatic/postzygotic contexts. Details ▾Hide ▴
Evidence considered
- No de novo germline report identified.
PP1 No co-segregation data available. The variant is predominantly somatic with no family studies reported. Details ▾Hide ▴
Evidence considered
- No co-segregation data in the literature.
PP4 No patient-specific phenotype or family history information available in the case materials. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No patient phenotype data in case materials.
Still missing
- Patient phenotype data not provided.
PP5 ClinVar classification is Pathogenic, but the aggregate review status is 'criteria provided, single submitter' (1-star). Per ACMG/AMP guidance, PP5 requires at least a 2-star review status (multiple submitters, no conflicts). The user's global PP5 rule specifies 3-star expert panel review is required for supporting-strength application. This variant has 12 submissions but no expert panel review; the review status does not meet the threshold. Details ▾Hide ▴
Evidence considered
- ClinVar: Pathogenic (12 submissions
- 8 clinical laboratories).
- Review status: criteria provided
- single submitter (1-star).
- No expert panel review
- does not meet 3-star PP5 threshold.
Sources
BA1 Variant is absent from gnomAD v2.1 (0/251,292) and nearly absent from v4.1 (1/1,613,126, AF=0.00006%). Far below the 1% BA1 threshold for a common benign variant. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.00%
- v4.1 AF=0.00006%
- both far below 1% BA1 threshold.
Sources
BS1 Variant is absent from gnomAD v2.1 (0/251,292) and nearly absent from v4.1 (1/1,613,126, AF=0.00006%). Far below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.00%
- v4.1 AF=0.00006%
- both far below 0.3% BS1 threshold.
Sources
BS2 No evidence of homozygous occurrence in healthy adults or observation in trans with a pathogenic variant. The single allele observed in gnomAD v4.1 is heterozygous and does not support a benign interpretation. Details ▾Hide ▴
Evidence considered
- No homozygous observations. Single gnomAD v4.1 allele is heterozygous.
Sources
BS3 All available functional evidence demonstrates a pathogenic gain-of-function effect (2-HG production, leukemogenesis promotion, drug sensitivity). No evidence supports a benign or neutral functional effect. See PS3 for detailed functional data. Details ▾Hide ▴
Evidence considered
- Functional studies uniformly demonstrate gain-of-function pathogenic effect
- no benign functional evidence exists.
Sources
BS4 No evidence of non-segregation with disease in family studies. No family data available in the case materials or literature. Details ▾Hide ▴
Evidence considered
- No segregation or non-segregation data available.
BP1 BP1 applies to missense variants in genes where primarily truncating variants cause disease through a loss-of-function mechanism. IDH1 disease is driven by gain-of-function missense mutations at specific active-site residues, not by loss-of-function. Truncating IDH1 variants are not the primary disease mechanism. Details ▾Hide ▴
Evidence considered
- IDH1 disease mechanism is gain-of-function via specific missense mutations
- truncating variants are not the primary disease mechanism.
Sources
pvs1_gene_context
BP2 No evidence of observation in trans with a known pathogenic dominant variant. No co-occurrence data available. Details ▾Hide ▴
Evidence considered
- No data on co-occurrence in trans with pathogenic variants.
BP4 Multiple in silico predictors support a damaging effect. REVEL score 0.814 (damaging), SpliceAI max delta 0.51 (possible splice impact). In silico evidence does not support a benign classification; it supports pathogenicity (see PP3). Details ▾Hide ▴
Evidence considered
- REVEL 0.814 predicts damaging. SpliceAI delta 0.51 suggests splice impact. Not benign.
Sources
revelspliceai ↗
BP5 No evidence that this variant is found in a case with an alternate molecular basis for disease. No such data available in the case materials. Details ▾Hide ▴
Evidence considered
- No alternate molecular cause identified.
BP6 ClinVar classification is Pathogenic, not benign. The review status is 'criteria provided, single submitter' (1-star), which does not meet the threshold for BP6 even if the classification were benign. Details ▾Hide ▴
Evidence considered
- ClinVar classification is Pathogenic
- BP6 not applicable. Review status is 1-star regardless.
Sources
BP7 BP7 applies to synonymous variants not predicted to affect splicing. NM_005896.3:c.394C>T is a missense variant (p.Arg132Cys), not a synonymous change. BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous. BP7 not applicable.
PS5 Not a standard ACMG/AMP 2015 criterion. In framework extensions where PS5 represents a well-established functional domain or multiple unrelated patients, this overlaps with PM1 (hotspot domain) and PS3 (functional data), both of which are scored independently. No independent evidence unique to PS5 is available beyond what has been captured under PM1 and PS3. Details ▾Hide ▴
Evidence considered
- PS5 is not a standard ACMG/AMP criterion
- evidence captured under PM1 and PS3.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense substitution; does not meet generic PVS1 null-variant criteria (nonsense, frameshift, or canonical ±1,2 splice variants) per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution c.394C>T (p.Arg132Cys) in exon 4. Not a predicted null variant.
Sources
pvs1_variant_assessmentpvs1_gene_context
PS1 N/ANo different nucleotide change at c.394 producing the same amino acid substitution (p.Arg132Cys) has been identified and established as pathogenic. PS1 requires a known pathogenic variant at the same position producing the identical amino acid change via a different nucleotide substitution. Details ▾Hide ▴
Evidence considered
- No alternative nucleotide change producing p.Arg132Cys identified in ClinVar or literature.
PP2 N/APP2 applies to genes where missense variants are a common mechanism of disease and the gene has a low rate of benign missense variation. IDH1 disease is driven by specific gain-of-function mutations at critical active-site residues, not by random missense constraint across the gene. PP2 is not appropriate for a gene with a highly restricted mutational spectrum. Details ▾Hide ▴
Evidence considered
- IDH1 pathogenic spectrum is restricted to specific active-site residues
- generalized missense constraint does not apply.
Identifiers
- Gene
- IDH1
- Transcript
- NM_005896.3
- Coding (HGVS c.)
- NM_005896.3:c.394C>T
- Protein (HGVS p.)
- NP_005887.2:p.(Arg132Cys)
- GRCh38
- chr2:208248389 G>A
- GRCh37
- chr2:209113113 G>A
- ClinVar
- 375891, 156444
- COSMIC
- COSV61615256
Gene diagram
Every interpreted variant in IDH1, mapped onto the exon structure of NM_005896.3. Select a row to find it on the plot.
IDH1NM_005896.3
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 IDH1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
1 / 1,613,126 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
0 / 251,292 alleles
AF 0 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,613,126 alleles · 0 hom
| European (non-Finnish)1 / 1,179,790 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 0 · 0 / 251,292 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19914e-07; MAF= 0.00006%, 1/1613126 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47608e-07; MAF= 0.00008%, 1/1179790 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251292 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16256 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.814
- BayesDel
- 0.415
How the predictions were used
PP3 SupportingMultiple in silico tools predict a deleterious effect. REVEL score of 0.814 exceeds the 0.5 threshold for a damaging prediction. SpliceAI max delta score of 0.51 suggests possible splice-altering potential. BayesDel score of 0.415 is borderline but the consensus of in silico predictors supports a pathogenic interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.814 (damaging).
- SpliceAI max delta: 0.51 (possible splice impact).
- BayesDel: 0.415 (borderline).
Sources
BP4 Multiple in silico predictors support a damaging effect. REVEL score 0.814 (damaging), SpliceAI max delta 0.51 (possible splice impact). In silico evidence does not support a benign classification; it supports pathogenicity (see PP3). Details ▾Hide ▴
Evidence considered
- REVEL 0.814 predicts damaging. SpliceAI delta 0.51 suggests splice impact. Not benign.
Sources
revelspliceai ↗
BP7 BP7 applies to synonymous variants not predicted to affect splicing. NM_005896.3:c.394C>T is a missense variant (p.Arg132Cys), not a synonymous change. BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous. BP7 not applicable.
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.51). REVEL score = 0.814. BayesDel score = 0.415345.
9 paper records listed. 3 cited in the classification.
Cited in the classification
-
PMID 19935646 ↗Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.Dang L et al. · 2009 Dec 10Demonstrated that cancer-associated mutations at IDH1 residue R132 (including R132H) produce the oncometabolite 2-hydroxyglutarate (2-HG), establishing the gain-of-function neomorphic mechanism. R132C was included among R132 mutations discussed, and cell lines expressing R132 mutant IDH1 showed elevated 2-HG levels.→ PS3 → PM1 → PM5 Names this variant
Source detail
These mutations occur at a single amino acid residue of IDH1, arginine 132, which is most commonly mutated to histidine (R132H).
Location Results; metabolite profiling and cell transfection experiments
Context U87MG glioblastoma cell transfection with R132 mutant IDH1; metabolite profiling by mass spectrometry
-
PMID 23954893 ↗Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML.Demonstrated that mutant IDH1 R132C promotes leukemogenesis in vivo. R132C cDNA was cloned from an MDS patient and tested in a mouse bone marrow transplantation model. R132C cooperated with HoxA9 to accelerate onset of MPD-like myeloid leukemia (median survival 83 days vs 167 days for wild-type IDH1, p<0.001). Mutant IDH1 activated MAPK signaling and repressed cyclin-dependent kinase inhibitors.→ PS3 Names this variant
Source detail
The 1.2-kb coding region of human IDH1 was amplified by nested polymerase chain reaction (PCR) from complementary DNA of bone marrow cells from an MDS syndrome patient with a heterozygous IDH1R132C mutation.
Location Methods ('Retroviral vectors and vector production' para 1); Results; Figures 1-4
Context Mouse bone marrow transplantation model (C57BL/6J); retroviral transduction of HoxA9-immortalized bone marrow cells; in vivo leukemogenesis assay
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PMID 29670690 ↗Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers.Describes the discovery and preclinical characterization of AG-120 (ivosidenib), a first-in-class mutant IDH1 inhibitor. AG-120 inhibited R132C with IC50 of 13 nM (enzyme) and 8 nM (HT1080 chondrosarcoma cells endogenously expressing R132C). The drug induced differentiation of primary R132C AML patient blasts ex vivo and reduced intracellular 2-HG by >96%.→ PS3 → PM5 Names this variant
Source detail
the potency for mIDH1-R132C is very similar to mIDH1-R132H, as previously reported
Location Results sections on biochemical profiling (Table 3), cellular assays, and ex vivo AML blast differentiation
Context Enzymatic assays on recombinant IDH1-R132C homodimer; HT1080 and COR-L105 cell lines endogenously expressing R132C; ex vivo primary AML blast cultures
Other recorded publications
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PMID 29860938 ↗Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML.Phase 1 clinical trial of ivosidenib (AG-120) in IDH1-mutated relapsed/refractory AML. Reports overall response rate of 41.6% and complete remission rate of 21.6% in IDH1-mutated AML patients. The abstract does not enumerate specific IDH1 variants; R132C is not specifically mentioned but is presumed to be included among IDH1-mutated patients given its known prevalence in AML.Does not name this variant
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PMID 22138009 ↗NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology.Febbo PG et al. · 2011NCCN Task Force report on evaluating clinical utility of tumor markers in oncology. Discusses biomarker frameworks across glioma, breast, colon, lung, prostate cancer, and AML. IDH1 is mentioned in the context of glioma molecular markers, but NM_005896.3:c.394C>T (R132C) was not specifically identified in this paper.Does not name this variant
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is the foundational methodology paper establishing the variant classification framework used in this assessment. Does not discuss IDH1 or the specific variant NM_005896.3:c.394C>T.Does not name this variant
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PMID 31409083 ↗Genetic Causes of Rare Pediatric Ovarian Tumors.Review of genetic causes of rare pediatric ovarian tumors. Notes that juvenile granulosa cell tumors in Ollier disease and Maffucci syndrome are caused by postzygotic IDH1 and IDH2 gene mutations. NM_005896.3:c.394C>T (p.Arg132Cys) was not specifically identified in this paper, though IDH1 mutations in general are discussed in the context of Ollier disease/Maffucci syndrome.Does not name this variant
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PMID 23619274 ↗American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.ACMG technical standards and guidelines for microarray analysis in neoplastic disorders. Does not discuss IDH1 sequence variants or NM_005896.3:c.394C>T.Does not name this variant
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PMID 27993330 ↗Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists.AMP/ASCO/CAP joint consensus recommendation for interpretation of sequence variants in cancer. Methodological guideline paper; does not discuss specific IDH1 variants.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,613,126 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.510
Open source ↗
ClinVar
8 Pathogenic · 1 pathogenic · 1 Likely pathogenic
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/375891/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-209113113-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-208248389-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-208248389-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005896.3%3Ac.394C…
- OncoKB ↗www.oncokb.org/gene/IDH1/R132C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=153664020
- Cancer hotspots ↗www.cancerhotspots.org/
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= 6.19914e-07; MAF= 0.00006%, 1/1613126 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47608e-07; MAF= 0.00008%, 1/1179790 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251292 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16256 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (8 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 375891)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.51). REVEL score = 0.814. BayesDel score = 0.415345.
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; COSV61615256, n = 1377 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.