Variant classification summary

NM_005896.4:c.394C>T

IDH1 · NP_005887.2:p.(Arg132Cys) · NM_005896.4

GRCh37: chr2:209113113 G>A · GRCh38: chr2:208248389 G>A

Gene: IDH1 Transcript: NM_005896.4

Final call

Likely Pathogenic

PS3 moderate PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

IDH1

Transcript

NM_005896.4

Protein

NP_005887.2:p.(Arg132Cys)

gnomAD AF

6.199143774261899e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 moderate: variant-specific functional studies support altered IDH1 activity and neomorphic 2-hydroxyglutarate production.

2

PM1 moderate: Arg132 is an IDH1 active-site residue and recurrent gain-of-function hotspot.

3

PM2 supporting: gnomAD frequency is below the supporting threshold.

4

PP3 supporting: REVEL 0.814 exceeds the generic missense threshold.

Final determination: Under generic ACMG/AMP 2015 fallback rules, 2 moderate pathogenic criteria plus 2 supporting pathogenic criteria lead to a Likely Pathogenic classification.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no independently established pathogenic alternate nucleotide change producing the same p.Arg132Cys amino-acid substitution was documented.	PMID:19935646
PS2	Not met	Not met: the variant was absent from the patient's peripheral blood and both parents, supporting tumor-restricted somatic rather than germline de novo occurrence.	PMID:37324278
PS3	Met	Met at moderate strength: recombinant R132C IDH1 produced the neomorphic 2-hydroxyglutarate activity, with independent R132C cellular and ex vivo confirmation.	PMID:19935646 PMID:29670690
PS4	Not met	Not met: AML cohort frequencies of 60% and 61% lack an unaffected-control comparison, so no valid PS4 odds ratio and 95% confidence interval can be calculated.	PMID:29860938 PMID:37324278 gnomad_v4
PM1	Met	Met, moderate: residue 132 is an IDH1 active-site position and a statistically significant R132 hotspot associated with gain-of-function mutations.	PMID:19935646 PMID:29670690 hotspots
PM2	Met	Met at supporting: gnomAD v3.1 non-cancer grpmax FAF is 0.0 and total AF is 6.79329e-06, below the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	N/A	Not applicable: the available evidence is somatic IDH1 p.(R132C) tumor data, not a recessive disorder with a pathogenic variant documented in trans.	PMID:37324278
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: alternate p.Arg132His, p.Arg132Leu, and p.Arg132Ser substitutions were reported, but independent pathogenic classification was not established.	PMID:19935646
PM6	Not met	Not met: tumor and enchondromatosis tissue carried the variant, but the patient's blood and both parents' blood were negative, indicating somatic tissue restriction.	PMID:37324278
PP1	Not assessed	Not assessed: no affected relatives with matching genotypes, phenotype concordance, or documented segregation data are available.
PP2	Not assessed	Not assessed: R132 missense disease mechanism is supported, but no gene-level benign-missense-rate threshold or analysis was provided.	PMID:19935646 gnomad_v4
PP3	Met	Met at supporting strength: REVEL 0.814 exceeds the PP3 supporting threshold of >=0.644 for this missense variant.	revel PMID:25741868
PP4	Not assessed	Not assessed: no defined case phenotype or family history is available to show a highly specific disease with a single genetic etiology.
PP5	Not met	Not met: ClinVar shows Pathogenic/Likely pathogenic laboratory assertions, but zero expert-panel submissions are present for this exact variant.	clinvar
BA1	Not met	Not met: gnomAD v3.1 non-cancer grpmax FAF is 0.0, far below the generic BA1 threshold of >=0.05.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: gnomAD v3.1 non-cancer grpmax FAF is 0.0, below the generic BS1 default threshold of >=0.01.	gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not assessed	Not assessed: gnomAD records one allele but do not establish a healthy adult, inheritance model, or early-age full penetrance.	gnomad_v4 gnomad_v2 PMID:25741868
BS3	Not met	Not met: R132C showed neomorphic 2-hydroxyglutarate production and mutant-specific cellular effects, not absence of damaging impact on IDH1 function.	PMID:19935646 PMID:29670690
BS4	Not assessed	Not assessed: no tested affected relatives are documented, so familial lack of segregation cannot be determined.
BP1	Not assessed	Not assessed: no gene-level disease spectrum showing that IDH1 disease is caused primarily by truncating variants was provided.	PMID:19935646
BP2	Not assessed	Not assessed: no second pathogenic variant or cis/trans phase is reported for the tumor-associated IDH1 p.(R132C) observation.	PMID:37324278
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.814 is above the BP4 supporting cutoff of <=0.29 for this missense variant.	revel PMID:25741868
BP5	Not met	Not met: the reported tumor case attributes the molecular finding to somatic IDH1 R132C and documents no separate alternate molecular basis for disease.	PMID:37324278
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present, and the record contains only non-expert assertions.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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