Classification rationale

PM2 BP4 VUS

MDM2 c.1270G>A

NM_002392.5:c.1270G>A (p.Glu424Lys) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population cohorts (PM2).¹ Multiple in silico predictors (REVEL 0.08, BayesDel -0.32377, SpliceAI max delta 0.00) consistently suggest no damaging effect on the MDM2 gene product (BP4).² No ClinVar entries, published functional studies, case-control data, or segregation data are available for this variant. One moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met, resulting in a variant of uncertain significance (VUS) under the generic ACMG/AMP 2015 classification framework (PMID:25741868).³

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelbayesdelspliceai ↗

3 generic_acmg_combination_rules

Gene diagram · NM_002392.5 · variants mapped to exon structure

MDM2 NM_002392.5

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 20 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 moderate Pathogenic

NM_002392.5:c.1270G>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (HostSeq genomes). Population frequency is 0.00%, well below the PM2 threshold of 0.1% for a gene without an expert panel framework.

gnomAD v2.1: absent (AC=nullAN=nullAF=null)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Multiple independent lines of computational evidence suggest no significant impact on the MDM2 gene product. REVEL score is 0.08 (well below the 0.5 threshold for pathogenic prediction), BayesDel additive score is -0.32377 (predicting benign), and SpliceAI predicts no splicing alteration (max delta score = 0.00). Three independent in silico predictors consistently indicate a neutral effect.

REVEL score: 0.08 — predicts benign (<0.5 threshold)BayesDel additive score: -0.32377 — predicts benign (negative score)SpliceAI max delta: 0.00 — no predicted splice alteration

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No pathogenic or likely pathogenic variant at the same amino acid residue (NP_002383.2:p.Glu424) has been identified in ClinVar.

PS2 No de novo observation with confirmed paternity and maternity has been reported for NM_002392.5:c.1270G>A.

PS3 No well-established functional studies demonstrating a damaging effect have been identified for NM_002392.5:c.1270G>A.

PS4 No case-control or cohort studies comparing variant prevalence in affected vs.

PM1 Residue p.Glu424 is not located in a statistically significant mutational hotspot as assessed by CancerHotspots.org.

PM6 No assumed de novo observation (without confirmed paternity and maternity) has been reported for NM_002392.5:c.1270G>A.

PP1 No co-segregation data are available for NM_002392.5:c.1270G>A.

PP2 PP2 requires a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3 Multiple lines of in silico computational evidence do not support a deleterious effect.

PP4 No patient phenotype or clinical history data are available for this variant.

PP5 PP5 is not a recognized criterion in the standard ACMG/AMP 2015 classification framework (Richards et al., PMID:25741868).

Benign

BA1 NM_002392.5:c.1270G>A is absent from all gnomAD population cohorts.

BS1 NM_002392.5:c.1270G>A is absent from all gnomAD population cohorts.

BS2 No data are available regarding observation of NM_002392.5:c.1270G>A in healthy adult individuals.

BS3 No well-established functional studies demonstrating no deleterious effect have been identified for NM_002392.5:c.1270G>A.

BS4 No data are available regarding lack of co-segregation with disease for NM_002392.5:c.1270G>A.

BP1 BP1 requires a missense variant in a gene for which primarily truncating variants are known to cause disease.

BP2 No data are available regarding observation of NM_002392.5:c.1270G>A in trans with a known pathogenic variant for a fully penetrant dominant disorder, or in cis with a known pathogenic variant.

BP5 No data are available regarding observation of NM_002392.5:c.1270G>A in a case with an alternative molecular basis for disease.

BP6 NM_002392.5:c.1270G>A is absent from ClinVar.

N/A · 3 PVS1 · PM5 · 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 = 0.08. BayesDel score = -0.32377.

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. MDM2, a ubiquitin ligase and p53 inhibitor, is amplified in a diverse range of cancers including well-differentiated liposarcomas.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

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