NM_002392.5:c.1036G>A (p.Glu346Lys) is a missense variant in MDM2, a proto-oncogene encoding a ubiquitin ligase and p53 inhibitor amplified in diverse cancers but lacking a well-established germline disease spectrum.1 The variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).2 Multiple in silico predictors are concordant in predicting a benign effect: REVEL 0.037, BayesDel -0.61515, and SpliceAI max delta 0.00 (BP4_Supporting).3 The variant is absent from ClinVar with no classifications, no functional studies, no case reports, and no segregation data available.4 Under generic ACMG/AMP 2015 combination rules (PMID:25741868), one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are present. These cancel, resulting in a classification of Variant of Uncertain Significance (VUS).5
MDM2
Final classification
VUS
MDM2 c.1036G>A · p.Glu346Lys
MDM2
NM_002392.5:c.1036G>A (p.Glu346Lys) is a missense variant in MDM2, a proto-oncogene encoding a ubiquitin ligase and p53 inhibitor amplified in diverse cancers but lacking a well-established germline disease spectrum.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
MDM2 c.1036G>A
PM2 + BP4
→
VUS
Gene diagram
· NM_002392.5 · variants mapped to exon structure
MDM2
NM_002392.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_002392.5:c.1036G>A is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), supporting rarity in the general population.
Absent from gnomAD v2.1 (search status: absent).Absent from gnomAD v4.1 (search status: absent).Absent from gnomAD-Canada v1.0 (search status: absent).
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no deleterious effect: REVEL score 0.037 (well below the pathogenic threshold of 0.5), BayesDel score -0.61515 (negative score predicts benign), and SpliceAI max delta 0.00 (no predicted splicing alteration). These three independent in silico predictors are concordant in predicting a benign effect.
REVEL: 0.037 (strongly benign-leaning).BayesDel: -0.61515 (benign prediction).SpliceAI: max delta 0.00 (no splicing impact predicted).
Assessed · not applied
Pathogenic
PS1
No known pathogenic variant with the same amino acid change (p.Glu346Lys) has been identified in ClinVar or the literature for MDM2.
PS2
No de novo observation with confirmed paternity and maternity has been reported for NM_002392.5:c.1036G>A.
PS3
No well-established functional studies demonstrate a damaging effect for NM_002392.5:c.1036G>A.
PS4
The variant is absent from ClinVar and no case-control studies comparing prevalence in affected individuals versus controls are available.
PM1
Residue p.Glu346 does not lie within a statistically significant mutational hotspot in Cancer Hotspots, nor is it located in a well-established critical functional domain with enrichment of pathogenic missense variation.
PM5
No pathogenic missense variant at the same residue (p.Glu346) has been identified in ClinVar to serve as a PM5 comparator.
PM6
No de novo observation (with or without confirmed parentage) has been reported for NM_002392.5:c.1036G>A.
PP1
No cosegregation data are available for NM_002392.5:c.1036G>A.
PP2
MDM2 is not a well-established Mendelian disease gene with a low rate of benign missense variation and missense variants as a common disease mechanism.
PP3
Multiple in silico predictors do not support a deleterious effect: REVEL score 0.037 (well below the 0.5 threshold), BayesDel score -0.61515 (negative scores indicate benign prediction), and SpliceAI max delta 0.00 (no predicted splicing impact).
PP4
No clinical phenotype or family history data are available for individuals carrying NM_002392.5:c.1036G>A.
PP5
No reputable source (clinical laboratory, expert panel, or database) classifies NM_002392.5:c.1036G>A as pathogenic.
Benign
BA1
NM_002392.5:c.1036G>A is absent from gnomAD v2.1 and v4.1.
BS1
NM_002392.5:c.1036G>A is absent from gnomAD v2.1 and v4.1.
BS2
No observation of NM_002392.5:c.1036G>A in healthy adult individuals has been reported in available data sources.
BS3
No well-established functional studies demonstrating a benign effect exist for NM_002392.5:c.1036G>A.
BS4
No segregation data are available to assess lack of cosegregation with disease for NM_002392.5:c.1036G>A.
BP1
BP1 requires a missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2
No observation of NM_002392.5:c.1036G>A in trans with a pathogenic variant in a fully penetrant dominant gene has been reported.
BP5
No alternative molecular basis for disease has been identified in a case with NM_002392.5:c.1036G>A.
BP6
No reputable source classifies NM_002392.5:c.1036G>A as benign.
N/A · 5
PVS1 · PM3 · 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
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.037. BayesDel score = -0.61515.
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.
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.
Sources & reference links