NM_002168.3:c.514A>G

IDH2 · NP_002159.2:p.(Arg172Gly) · NM_002168.3

GRCh37: chr15:90631839 T>C · GRCh38: chr15:90088607 T>C

Gene: IDH2 Transcript: NM_002168.3

Final call

Pathogenic

PS3 strong PM1 moderate PM2 moderate PP3 supporting PP5 supporting

Variant details

Gene

IDH2

Transcript

NM_002168.3

Protein

NP_002159.2:p.(Arg172Gly)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

PS3 (strong): Two independent publications (PMID:21641335, PMID:22309944) directly tested the exact IDH2 R172G variant, demonstrating loss of wild-type enzymatic activity and gain of neomorphic 2-hydroxyglutarate production.

PM1 (moderate): Variant is located at arginine 172, the catalytic active-site residue in IDH2 and a statistically significant mutational hotspot (cancerhotspots.org).

PM2 (moderate): Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0.0).

PP3 (supporting): REVEL score 0.669 predicts a deleterious effect on protein function.

PP5 (supporting): Reported as Likely pathogenic in ClinVar by a clinical diagnostic laboratory with criteria provided (Variation ID: 376439).

Overall classification: Pathogenic. The combination of 1 strong criterion (PS3), 2 moderate criteria (PM1, PM2), and 2 supporting criteria (PP3, PP5) satisfies the generic ACMG/AMP 2015 pathogenic threshold (1 Strong + 2 Moderate + 2 Supporting).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting pathogenic criteria.

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	Missense variant (c.514A>G, p.Arg172Gly) does not meet ClinGen SVI PVS1 null-variant criteria: not a nonsense, frameshift, or canonical ±1,2 splice consensus variant. Generic PVS1 framework does not apply.	pvs1_generic_framework
PS1	Not met	No evidence of a different nucleotide change at c.514 resulting in the same p.Arg172Gly amino acid substitution. PS1 requires co-location with a known pathogenic variant causing the identical amino acid change via a different nucleotide substitution.
PS2	Not met	No evidence of confirmed de novo occurrence with both maternity and paternity confirmed.
PS3	Met	Two independent publications directly tested the exact IDH2 R172G variant in cell line models, demonstrating loss of wild-type enzymatic activity and gain of neomorphic oncogenic function. PMID:21641335 showed that IDH2 R172G diminishes NADPH production and alters cellular proliferation. PMID:22309944 showed that IDH2 R172G overexpression induces HIF-1α upregulation and β-catenin nuclear accumulation. The neomorphic gain-of-function (2-hydroxyglutarate production) is a well-established consequence of IDH2 R172 mutations, corroborated by PMID:21326614 for the broader R172 class.	PMID:21641335 PMID:22309944
PS4	Not met	No case-control data comparing variant prevalence in affected individuals versus the general population. COSMIC reports 48 somatic cancer occurrences, but these are not suitable for germline PS4 case-control analysis.
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion. The standard framework does not include this criterion code.
PM1	Met	Variant is located at arginine 172, the catalytic active-site residue in IDH2 (analogous to IDH1 R132). This is a well-established critical functional domain in the enzyme active site and a statistically significant mutational hotspot (cancerhotspots.org). ClinVar submission SCV005902248 independently cites PM1 for this variant.	clinvar PMID:21326614
PM2	Met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (allele frequency = 0.0). Meets PM2 threshold of <0.1% for non-VCEP generic ACMG application.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	While other pathogenic missense changes at codon 172 are known (R172K, R172M in gliomas; R172W in AML), no same-residue comparator variants with germline pathogenic classification were confirmed in the case evidence. The automated PM5 candidate search returned no qualifying candidates. Literature evidence for other R172 substitutions exists only in somatic cancer context.
PM6	Not met	No de novo observation data available. PM6 requires assumed de novo occurrence without confirmation of paternity and maternity.
PP1	Not met	No segregation data available. PP1 requires co-segregation with disease in multiple affected family members.
PP2	Not met	HCI prior scores are not available for IDH2. Insufficient data to establish that missense variants are a common mechanism of disease for this gene in a germline context. PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism.
PP3	Met	REVEL score 0.669 predicts a deleterious effect on protein function (>0.5 threshold). SpliceAI predicts no splice impact (max delta 0.03). Multiple in silico tools support a deleterious effect, though BayesDel (0.383) is borderline. Overall evidence supports a damaging in silico prediction.	revel spliceai bayesdel
PP4	Not met	No phenotype specificity data available for this variant in a germline context. PP4 requires the variant to be found in a patient whose phenotype or family history is highly specific for the disease.
PP5	Met	Reported as Likely pathogenic in ClinVar (Variation ID: 376439) by Clinical Genomics Laboratory, Washington University in St. Louis (SCV005902248, criteria provided, single submitter). A reputable clinical laboratory has classified this variant as likely pathogenic with supporting criteria; while a single-submitter submission without expert panel review carries less weight than a 3-star classification, the criteria-provided submission from a clinical diagnostic laboratory satisfies PP5 at supporting strength under generic ACMG.	clinvar
BA1	Not met	Variant is absent from gnomAD. Does not meet BA1 threshold of >1% (or >5%) allele frequency in population databases.	gnomad_v2 gnomad_v4
BS1	Not met	Variant is absent from gnomAD. Does not meet BS1 threshold of >0.3% allele frequency for non-VCEP generic ACMG application.	gnomad_v2 gnomad_v4
BS2	Not met	No observations in homozygous state in population controls. BS2 requires observation in a healthy adult in a homozygous state for a fully penetrant dominant disorder.
BS3	Not met	Functional studies demonstrate a deleterious effect: loss of wild-type enzymatic activity and gain of neomorphic 2-hydroxyglutarate production (PMID:21641335, PMID:22309944). These findings are inconsistent with a benign interpretation; BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect.	PMID:21641335 PMID:22309944 PMID:21326614
BS4	Not met	No segregation data available demonstrating non-segregation with disease. BS4 requires lack of segregation in affected family members.
BP1	Not met	IDH2 has known pathogenic missense variants at codon 172 (R172K, R172M in gliomas; R172W in AML). BP1 applies only to genes where missense variants are not a known disease mechanism and the primary mechanism is truncating variants.	PMID:21326614
BP2	Not met	No observation of this variant in trans with a known pathogenic variant. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP4	Not met	REVEL score 0.669 predicts a deleterious effect; multiple computational tools suggest a damaging impact. BP4 requires multiple lines of computational evidence suggesting no impact on gene product. The in silico evidence supports a deleterious prediction.	revel bayesdel
BP5	Not met	No case identified where this variant is found in an individual with an alternate molecular basis for disease. BP5 requires observation in a case with an established alternate cause.
BP6	Not met	ClinVar classification for this variant is Likely pathogenic, not benign. BP6 requires a reputable source to report the variant as benign.	clinvar
BP7	N/A	This is a missense variant (c.514A>G, p.Arg172Gly). BP7 applies only to synonymous (silent) variants with no predicted splice impact.
BP3	N/A	In-frame deletion/insertion criterion; variant is a substitution.
PM3	N/A	Recessive disorder criterion; IDH2-associated conditions are not recessively inherited.
PM4	N/A	Protein length change criterion; variant is a substitution.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.