NM_002168.3:c.413C>A

IDH2 · NP_002159.2:p.(Thr138Asn) · NM_002168.3

GRCh37: chr15:90631940 G>T · GRCh38: chr15:90088708 G>T

Gene: IDH2 Transcript: NM_002168.3

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

IDH2

Transcript

NM_002168.3

Protein

NP_002159.2:p.(Thr138Asn)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada, AF = 0, below the 0.1% threshold.

PP3 (Supporting): REVEL 0.736 crosses the ClinGen SVI supporting-pathogenic threshold (>=0.644).

PM2 supporting plus PP3 supporting satisfies no ACMG/AMP 2015 combination rule, yielding Variant of Uncertain Significance.

Final determination: Under the generic ACMG/AMP 2015 fallback (PMID:25741868), PM2 supporting + PP3 supporting (2 supporting, 0 benign) meets no pathogenic, likely pathogenic, benign, or likely benign combination threshold; all other combinations, including this one, default to 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: this is a missense substitution, so no null-variant mechanism such as nonsense-mediated decay is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no established pathogenic variant causing the same amino-acid change (p.Thr138Asn) exists for comparison.	generic_acmg_combination_rules clinvar pm5_candidates
PS2	Not assessed	Not assessed: no de novo occurrence or parental genotyping data for this variant was available.	clinvar generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no functional assay evidence was available; only computational predictions (REVEL 0.736, BayesDel -0.038).	oncokb spliceai revel bayesdel generic_acmg_combination_rules
PS4	Not assessed	Not assessed: no case-control data existed; only a single somatic COSMIC observation (n=1) was found.	clinvar gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM1	Not met	Not met: residue Thr138 is not a statistically significant hotspot, and OncoKB hotspots are Arg140/Arg172.	generic_acmg_combination_rules oncokb gnomad_v2 gnomad_v4
PM2	Met	Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF = 0, below the 0.1% threshold).	gnomad_v2 gnomad_v4 gnomad_canada clinvar generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no proband, allele-phase, or trans data was available to evaluate recessive inheritance.	generic_acmg_combination_rules clinvar gnomad_v2 gnomad_v4
PM4	N/A	Not applicable: missense substitution, so no protein length change occurs.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: no different missense change at residue Thr138 has been classified pathogenic.	generic_acmg_combination_rules clinvar pm5_candidates
PM6	Not assessed	Not assessed: no de novo occurrence of this variant has been reported.	clinvar generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no family segregation or meioses-count data was available.	clinvar generic_acmg_combination_rules
PP2	Not assessed	Not assessed: no gene-level missense constraint data (e.g., gnomAD Z-score) was available.	generic_acmg_combination_rules oncokb
PP3	Met	Met (supporting): REVEL 0.736 crosses the ClinGen SVI supporting-pathogenic threshold (>=0.644).	revel bayesdel spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family-history data was available.	generic_acmg_combination_rules
PP5	Not met	Not met: ClinVar has no entry for this variant, so no expert-panel pathogenic classification exists.	clinvar generic_acmg_combination_rules
BA1	Not met	Not met: allele frequency is 0 in every gnomAD cohort, far below the 1% threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: allele frequency is 0, so the variant cannot exceed the 0.3% expected-frequency threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS2	Not met	Not met: no healthy-adult carriers or homozygotes were observed in any population cohort.	gnomad_v2 gnomad_v4 gnomad_canada clinvar generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no functional studies showing no damaging effect on protein function were available.	oncokb spliceai revel bayesdel generic_acmg_combination_rules
BS4	Not assessed	Not assessed: no family genotyping or allele-phase data was available.	clinvar generic_acmg_combination_rules
BP1	Not met	Not met: IDH2 disease mechanism is gain-of-function missense, not primarily truncating.	generic_acmg_combination_rules oncokb pvs1_gene_context
BP2	Not assessed	Not assessed: no allele-phase evidence (cis/trans) was available.	generic_acmg_combination_rules clinvar gnomad_v2 gnomad_v4
BP3	N/A	Not applicable: missense substitution, not an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: only SpliceAI predicts no impact (max delta 0.00); REVEL 0.736 contradicts a benign call.	spliceai revel bayesdel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband workup data existed to identify an alternate molecular basis of disease.	generic_acmg_combination_rules
BP6	Not met	Not met: ClinVar has no entry for this variant, so no expert-panel benign classification exists.	clinvar generic_acmg_combination_rules
BP7	N/A	Not applicable: missense substitution, so the silent-variant premise does not hold.	generic_acmg_combination_rules

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.