Classification rationale

PM2PP3 VUS

IDH2 c.413C>A

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.

PM2 + PP3 → VUS

Gene diagram · NM_002168.3 · variants mapped to exon structure

IDH2 NM_002168.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 22 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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

gnomAD v2.1: variant 15-90631940-G-T absent (search_status=absent) — AF 0 < 0.1%gnomAD v4.1: variant 15-90088708-G-T absent (search_status=absent) — AF 0 < 0.1%gnomAD-Canada v1.0: variant 15-90088708-G-T absent (search_status=absent)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗clinvar ↗

✓

PP3 supporting Pathogenic

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

REVEL score 0.736 (local lookup, revel-v1.3 chrom15; verified ClinGen SVI calibration, PMID 36413997) - >=0.644 supporting-pathogenic tier, <0.773 moderate tier; predicts deleterious missense effectBayesDel noAF score -0.037745 (local lookup, BayesDel_170824_noAF chr15) - 0.0 points (neutral band 0.06 to -0.18) in the pipeline SVCv4 ladder; PLACEHOLDER calibration, contributes no PP3 or BP4 signalSpliceAI max delta 0.00 (DS_AG=DS_AL=DS_DG=DS_DL=0.0; variant_consequence=sequence_variant) - no predicted splice impact; neutral for the missense PP3 path

spliceai ↗

Assessed · not applied

Pathogenic

PS1 Not met: no established pathogenic variant causing the same amino-acid change (p.Thr138Asn) exists for comparison.

PS2 Not assessed: no de novo occurrence or parental genotyping data for this variant was available.

PS3 Not assessed: no functional assay evidence was available; only computational predictions (REVEL 0.736, BayesDel -0.038).

PS4 Not assessed: no case-control data existed; only a single somatic COSMIC observation (n=1) was found.

PM1 Not met: residue Thr138 is not a statistically significant hotspot, and OncoKB hotspots are Arg140/Arg172.

PM3 Not assessed: no proband, allele-phase, or trans data was available to evaluate recessive inheritance.

PM5 Not met: no different missense change at residue Thr138 has been classified pathogenic.

PM6 Not assessed: no de novo occurrence of this variant has been reported.

PP1 Not assessed: no family segregation or meioses-count data was available.

PP2 Not assessed: no gene-level missense constraint data (e.g., gnomAD Z-score) was available.

PP4 Not assessed: no proband phenotype or family-history data was available.

PP5 Not met: ClinVar has no entry for this variant, so no expert-panel pathogenic classification exists.

Benign

BA1 Not met: allele frequency is 0 in every gnomAD cohort, far below the 1% threshold.

BS1 Not met: allele frequency is 0, so the variant cannot exceed the 0.3% expected-frequency threshold.

BS2 Not met: no healthy-adult carriers or homozygotes were observed in any population cohort.

BS3 Not assessed: no functional studies showing no damaging effect on protein function were available.

BS4 Not assessed: no family genotyping or allele-phase data was available.

BP1 Not met: IDH2 disease mechanism is gain-of-function missense, not primarily truncating.

BP2 Not assessed: no allele-phase evidence (cis/trans) was available.

BP4 Not met: only SpliceAI predicts no impact (max delta 0.00); REVEL 0.736 contradicts a benign call.

BP5 Not assessed: no proband workup data existed to identify an alternate molecular basis of disease.

BP6 Not met: ClinVar has no entry for this variant, so no expert-panel benign classification exists.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.736. BayesDel score = -0.037745.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. IDH2, a cell metabolism enzyme, is recurrently mutated in various cancer types including acute myeloid leukemia, glioblastoma, and cholangiocarcinoma.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV100344117, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots