NM_002392.5:c.500G>A (NP_002383.2:p.Arg167Lys) is a missense variant in MDM2 that is absent from all gnomAD population databases (v2.1, v4.1, and gnomAD-Canada), meeting PM2 at supporting level.1 Multiple in silico tools uniformly predict a tolerated or benign effect: REVEL score 0.144, BayesDel score -0.333371, and SpliceAI max delta 0.00, meeting BP4 at supporting benign level.2 The variant is absent from ClinVar, COSMIC, and the published literature. No functional studies, segregation data, de novo reports, or case-control data are available. No CSPEC/VCEP framework exists for MDM2.3 With PM2 (supporting pathogenic) and BP4 (supporting benign) as the only met criteria and all other criteria not assessed, the evidence is insufficient for classification. The variant is classified as a Variant of Uncertain Significance (VUS) per generic ACMG/AMP 2015 criteria.4
MDM2
Final classification
VUS
MDM2 c.500G>A · p.Arg167Lys
MDM2
NM_002392.5:c.500G>A (NP_002383.2:p.Arg167Lys) is a missense variant in MDM2 that is absent from all gnomAD population databases (v2.1, v4.1, and gnomAD-Canada), meeting PM2 at supporting level.
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.500G>A
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
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
supporting
Pathogenic
This variant is absent from all gnomAD population databases (v2.1 exomes, v4.1 exomes, and gnomAD-Canada v1.0 genomes), satisfying the non-VCEP PM2 threshold of allele frequency <0.1%.
gnomAD v2.1: absent (AF <0.1%)gnomAD v4.1: absent (AF <0.1%)gnomAD-Canada v1.0: absent (AF=0.0)
✓
BP4
supporting
Benign
Multiple lines of computational evidence uniformly suggest no deleterious impact: REVEL score 0.144, BayesDel score -0.333371 (tolerated), and SpliceAI predicts no splice alteration (max delta 0.00). This satisfies BP4 at the supporting benign level.
REVEL: 0.144 (benign/tolerated range)BayesDel: -0.333371 (tolerated)SpliceAI max delta: 0.00 (no predicted splice impact)
Assessed · not applied
Pathogenic
PS1
No known pathogenic variant with a different nucleotide change at Arg167 was identified in ClinVar or the literature.
PS2
No de novo data with confirmed paternity and maternity are available for this variant.
PS3
No well-established in vitro or in vivo functional studies were identified for NM_002392.5:c.500G>A.
PS4
No case-control or prevalence data are available.
PM1
The variant is not located in a statistically significant mutational hotspot per CancerHotspots.
PM6
No de novo reports (with or without confirmed parentage) are available for this variant.
PP1
No co-segregation data are available for this variant.
PP2
Constraint metrics are not available for MDM2 (HCI Prior lookup returned gene not supported).
PP3
Multiple in silico tools uniformly predict a benign or tolerated effect: REVEL score 0.144 (below typical damaging threshold of 0.5), BayesDel score -0.333371 (negative, indicating tolerated), and SpliceAI max delta 0.00 (no splice impact).
PP4
No patient phenotype or family history data are available to support variant-specific phenotyping.
PP5
The variant is absent from ClinVar; no reputable source has issued a pathogenic classification.
Benign
BA1
The variant is absent from all gnomAD datasets (v2.1, v4.1, Canada).
BS1
The variant is absent from all gnomAD datasets; allele frequency of 0% is far below the non-VCEP BS1 threshold of >0.3%.
BS2
No data are available regarding observation of this variant in healthy adult individuals.
BS3
No well-established in vitro or in vivo functional studies showing no deleterious effect were identified for this variant.
BS4
No non-segregation data are available for this variant.
BP1
BP1 requires a gene where only truncating variants cause disease.
BP2
No data are available regarding observation of this variant in trans with a known pathogenic variant.
BP5
No alternative molecular cause has been identified in the case materials.
BP6
The variant is absent from ClinVar; no reputable source has issued a benign classification.
N/A · 6
PVS1 · PM3 · PM4 · PM5 · 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 = 0.144. BayesDel score = -0.333371.
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