LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-10
Case ID: NM_002168.3_c.520G_A_20260810_072939
Framework: ACMG/AMP 2015
Variant classification summary

NM_002168.3:c.520G>A

IDH2  · NP_002159.2:p.(Ala174Thr)  · NM_002168.3
GRCh37: chr15:90631833 C>T  ·  GRCh38: chr15:90088601 C>T
Gene: IDH2 Transcript: NM_002168.3
Final call
VUS
PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
IDH2
Transcript
NM_002168.3
Protein
NP_002159.2:p.(Ala174Thr)
gnomAD AF
6.195034555902752e-07 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PM2 (Supporting): absent from gnomAD v2.1 and gnomAD-Canada, with a single allele in 1,614,196 (AF 6.2e-07), far below the 0.1% low-frequency threshold.
2
Overall classification: Variant of Uncertain Significance — a single supporting criterion satisfies no pathogenic or benign combination threshold under the generic ACMG/AMP 2015 rules.
Final determination: Generic ACMG/AMP 2015 fallback combination rules (PMID:25741868): with only one supporting pathogenic criterion (PM2 supporting) and no benign criteria met, none of the Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination thresholds is satisfied, and the variant is therefore 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 Not applicable: c.520G>A is a missense change, and PVS1 applies only to null variants expected to trigger nonsense-mediated decay.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not met Not met: no different-nucleotide change producing p.Ala174Thr with a pathogenic assertion exists in ClinVar or the literature.
clinvar pm5_candidates generic_acmg_combination_rules
PS2 Not assessed Not assessed: no proband-parent trio or parental testing data were available to evaluate a de novo origin.
clinvar generic_acmg_combination_rules
PS3 Not assessed Not assessed: no functional studies of this variant (enzyme, cellular, or animal assays) were available.
oncokb generic_acmg_combination_rules PMID:23169492 PMID:25626707 PMID:25730230
PS4 Not met Not met: no case-control enrichment evidence exists; the variant is essentially absent from population controls (gnomAD AF 6.2e-07).
clinvar gnomad_v4 gnomad_v2 gnomad_canada oncokb PMID:23169492 PMID:25626707 PMID:25730230
PM1 Not met Not met: residue 174 is not a hotspot; IDH2's established hotspots are catalytic residues R140 and R172.
oncokb gnomad_v4 gnomad_v2 generic_acmg_combination_rules
PM2 Met Met (supporting): absent from gnomAD v2.1 and gnomAD-Canada, with a single allele in 1,614,196 (AF 6.2e-07) — far below the 0.1% PM2 threshold.
gnomad_v4 gnomad_v2 gnomad_canada generic_acmg_combination_rules
PM3 Not met Not met: no observation of this variant in trans with a pathogenic IDH2 variant was available.
clinvar gnomad_v4 gnomad_v2 gnomad_canada PMID:25626707 PMID:25730230 PMID:23169492 PMID:22947299 PMID:23881473
PM4 N/A Not applicable: PM4 covers protein length changes; this missense substitution alters no protein length.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not assessed Not assessed: no pathogenic alternate missense at residue 174 was identified, so a different-missense comparator could not be confirmed.
pm5_candidates clinvar generic_acmg_combination_rules
PM6 Not assessed Not assessed: no de novo occurrence or parental testing is documented for this variant.
clinvar generic_acmg_combination_rules
PP1 Not assessed Not assessed: no family segregation or pedigree data were available.
clinvar generic_acmg_combination_rules
PP2 Not assessed Not assessed: no gene-level missense constraint metric (gnomAD Z-score) was available to evaluate PP2.
oncokb generic_acmg_combination_rules
PP3 Not met Not met: REVEL 0.749 is below the calibrated 0.773 PP3-supporting threshold.
revel spliceai bayesdel
PP4 Not assessed Not assessed: no proband phenotype or family history data were available to evaluate phenotype specificity.
clinvar PMID:23169492 PMID:25626707 PMID:25730230
PP5 Not met Not met: ClinVar holds only a single-submitter laboratory VUS, with no expert-panel pathogenic classification.
clinvar
BA1 Not met Not met: gnomAD AF 6.2e-07 is roughly five orders of magnitude below the >1% BA1 threshold.
gnomad_v4 gnomad_v2 gnomad_canada generic_acmg_combination_rules
BS1 Not met Not met: gnomAD AF 6.2e-07 is orders of magnitude below the >0.3% BS1 threshold.
gnomad_v4 gnomad_v2 gnomad_canada generic_acmg_combination_rules
BS2 Not met Not met: zero homozygotes observed across 1,614,196 gnomAD v4.1 alleles.
gnomad_v4 gnomad_v2 gnomad_canada generic_acmg_combination_rules
BS3 Not assessed Not assessed: no functional studies demonstrating absence of a damaging effect were available.
spliceai oncokb generic_acmg_combination_rules PMID:23169492 PMID:25626707 PMID:25730230
BS4 Not assessed Not assessed: no family or segregation evidence showing non-segregation was available.
clinvar generic_acmg_combination_rules gnomad_v4
BP1 N/A Not applicable: IDH2 disease is driven by missense gain-of-function variants, not truncating variants.
oncokb pvs1_gene_context generic_acmg_combination_rules
BP2 Not met Not met: no observation in trans or cis with a pathogenic IDH2 variant was available.
clinvar gnomad_v4 gnomad_v2 gnomad_canada PMID:25626707 PMID:25730230 PMID:23169492 PMID:22947299 PMID:23881473
BP3 N/A Not applicable: BP3 covers in-frame indels in repetitive regions; this is a missense substitution.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: REVEL 0.749 far exceeds the calibrated 0.128 BP4-supporting threshold.
revel spliceai bayesdel
BP5 Not met Not met: no reported case carries this variant with an alternate molecular basis for disease.
clinvar PMID:23169492 PMID:25626707 PMID:25730230
BP6 Not met Not met: ClinVar holds only a single-submitter laboratory VUS, with no expert-panel benign classification.
clinvar
BP7 N/A Not applicable: BP7 applies to synonymous variants; this is a missense substitution.
generic_acmg_combination_rules
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