NM_002168.3:c.516G>C

IDH2 · NP_002159.2:p.(Arg172Ser) · NM_002168.3

GRCh37: chr15:90631837 C>G · GRCh38: chr15:90088605 C>G

Gene: IDH2 Transcript: NM_002168.3

Final call

VUS

PM1 supporting PM2 supporting

Variant details

Gene

IDH2

Transcript

NM_002168.3

Protein

NP_002159.2:p.(Arg172Ser)

gnomAD AF

6.19492709809791e-07 (v4.1)

ClinVar

risk factor

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

PM1 (supporting): p.Arg172 is the critical active site residue of IDH2, a well-characterized functional domain and statistically significant mutational hotspot where somatic missense mutations produce neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate. OncoKB classifies R172S as oncogenic, and PMID:24403254 confirmed R172S as a recurrent somatic mutation in 3/12 osteosarcoma patients.

PM2 (supporting): NM_002168.3:c.516G>C is absent from gnomAD v2.1 and extremely rare in gnomAD v4.1 (AF = 6.19 × 10⁻⁷; 1/1,614,224 alleles; 0 homozygotes), far below the PM2 threshold of <0.1%.

Two supporting criteria for pathogenicity (PM1_supporting + PM2_supporting) are met with no benign criteria met. Per the generic ACMG/AMP 2015 classification combination rules (PMID:25741868), this combination does not reach the threshold for Likely Pathogenic (minimum requires ≥1 moderate and ≥4 supporting, or ≥2 moderate and ≥2 supporting, or ≥1 strong and ≥2 supporting). The variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	NM_002168.3:c.516G>C is a missense variant (p.Arg172Ser); it does not fall into the generic PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants). PVS1 is not applicable to missense variants under the ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework
PS1	Not met	No evidence that a different nucleotide change at c.516 leading to the same p.Arg172Ser amino acid substitution has been established as pathogenic. The ClinVar record (375985) is for this exact nucleotide change and is classified as risk factor with no assertion criteria provided.	clinvar
PS2	Not met	No de novo data available for this variant. No case reports or family studies documenting confirmed de novo occurrence of NM_002168.3:c.516G>C.
PS3	Not met	No variant-specific functional assay demonstrating a deleterious effect for p.Arg172Ser (R172S) was identified. PMID:20171147 demonstrated neomorphic 2HG-producing activity for IDH2 R172 mutants but specifically tested R172K, not R172S. PMID:24403254 identified R172S in 3/12 osteosarcoma patients and performed antibody-based detection (MsMab-1) but reported no morphological or growth difference between IDH2-WT and IDH2-R172S in transfected U-2 OS cells. No systematic saturation mutagenesis or tiling screen at residue R172 has characterized R172S. Domain-level inference from sparse testing qualifies for PM1, not PS3.	PMID:20171147 PMID:24403254
PS4	Not met	No case-control data comparing variant prevalence in affected individuals versus controls. The ClinVar submission (SCV002047547) is from a case-control study but is classified as somatic origin with risk factor classification and no assertion criteria provided. This does not satisfy PS4 requirements.	clinvar
PS5	N/A	PS5 applies when two pathogenic variants are observed in trans for recessive disorders. No recessive disease context has been established for IDH2, and no trans configuration data exists.
PM1	Met	p.Arg172 is the critical active site residue of IDH2, analogous to IDH1 R132. This residue is a well-characterized functional domain where somatic missense mutations (R172K, R172M, R172W, R172G, R172S) produce neomorphic enzyme activity converting α-ketoglutarate to the oncometabolite 2-hydroxyglutarate. The residue is in a statistically significant mutational hotspot (cancerhotspots.org), OncoKB classifies R172S as oncogenic, and PMID:24403254 confirmed R172S as a recurrent somatic mutation in osteosarcoma (3/12 patients).	oncokb PMID:24403254
PM2	Met	NM_002168.3:c.516G>C is absent from gnomAD v2.1 and extremely rare in gnomAD v4.1 (AF = 6.19 × 10⁻⁷; 1/1,614,224 alleles; 0 homozygotes). The highest subpopulation frequency is in Ashkenazi Jewish (AF = 3.38 × 10⁻⁵; 1/29,606 alleles). Allele frequency is far below the PM2 threshold of <0.1% in all populations, consistent with a rare variant.	gnomad_v2 gnomad_v4
PM5	Not met	No same-residue pathogenic comparator with a different amino acid change was identified in ClinVar. While the literature describes R172K, R172M, R172W, and R172G as recurrent IDH2 mutations in gliomas and AML, automated PM5 candidate harvesting found no eligible ClinVar entries with expert panel or majority pathogenic classification at this codon. Without a ClinVar-confirmed pathogenic comparator at the same residue with a different amino acid change, PM5 cannot be applied.	pm5_candidates
PM6	Not met	No de novo data available. No publications or ClinVar submissions report confirmed de novo occurrence of NM_002168.3:c.516G>C with confirmed maternity and paternity.
PP1	Not met	No co-segregation data available. No family studies have been conducted for this variant.
PP2	Not met	IDH2 disease mechanism is predominantly gain-of-function/neomorphic via missense mutations at specific active site residues (R172, R140), not a gene where a low rate of benign missense variation and high missense constraint is the defining feature. The gene does not meet the typical PP2 profile of a gene where missense variants are a common mechanism of disease with low benign missense tolerance in population databases.
PP3	Not met	In silico predictions are mixed and do not provide multiple lines of computational support for a deleterious effect. REVEL score is 0.567 (moderate, below the typical damaging threshold of >0.7). BayesDel score is 0.31655 (low, not predicted damaging). SpliceAI max delta is 0.01 (no predicted splice impact). Only one tool (REVEL) shows moderate evidence, which is insufficient for PP3.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or clinical data available for this variant. The ClinVar submission is of somatic origin (risk factor) and provides no germline phenotype information.
PP5	Not met	ClinVar classification for this variant (VariationID 375985) is risk factor with review status 'no assertion criteria provided' (0-star). PP5 requires a reputable source with 3-star expert panel review to be applied at supporting strength. The single ClinVar submission (SCV002047547) is from a non-clinical testing source without assertion criteria, and does not qualify for PP5.	clinvar
BA1	Not met	Variant allele frequency in gnomAD v4.1 is 6.19 × 10⁻⁷ (0.00006%), far below the BA1 threshold of >1%. Variant is absent from gnomAD v2.1.	gnomad_v2 gnomad_v4
BS1	Not met	Variant allele frequency in gnomAD v4.1 is 6.19 × 10⁻⁷ (0.00006%), far below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No data on observation of this variant in healthy adults. The single gnomAD allele (1/1,614,224) is insufficient to establish BS2, as a single observation does not confirm healthy adult status.
BS3	Not met	Well-established functional studies (PMID:20171147, PMID:23264629) demonstrate that IDH2 R172 mutations produce a neomorphic gain-of-function — converting α-ketoglutarate to the oncometabolite 2-hydroxyglutarate — rather than showing no damaging effect. The literature does not support a benign functional interpretation for IDH2 R172 mutations.	PMID:20171147 PMID:23264629
BS4	Not met	No segregation data available to demonstrate lack of co-segregation with disease.
BP1	Not met	IDH2 disease mechanism is predominantly gain-of-function/neomorphic via specific missense mutations at active site residues. BP1 applies to genes where primarily truncating variants cause disease and missense variants are less likely to be pathogenic. IDH2 does not fit this profile; the known pathogenic mechanism is missense-based neomorphic activity.
BP2	Not met	No data on observation in trans with a pathogenic variant. The variant is extremely rare and no trans configuration data exists.
BP3	N/A	NM_002168.3:c.516G>C is a single-nucleotide substitution (missense), not an in-frame deletion or insertion in a repetitive region.
BP4	Not met	Computational evidence does not support a benign interpretation. REVEL score is 0.567 (moderate, not clearly benign), BayesDel is 0.31655, and SpliceAI shows no splice impact. The in silico evidence is mixed and does not provide multiple lines of evidence suggesting no impact.	revel bayesdel spliceai
BP5	Not met	No data indicating this variant is found in a case with an alternate molecular basis for disease.
BP6	Not met	ClinVar classification is risk factor, not benign. Review status is 'no assertion criteria provided' (0-star). BP6 requires a reputable source classifying the variant as benign with strong supporting evidence. The available ClinVar entry does not meet this threshold.	clinvar
BP7	N/A	NM_002168.3:c.516G>C is a missense variant (p.Arg172Ser), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.

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