NM_002392.5:c.500G>A

MDM2 · NP_002383.2:p.(Arg167Lys) · NM_002392.5

GRCh37: chr12:69218408 G>A · GRCh38: chr12:68824628 G>A

Gene: MDM2 Transcript: NM_002392.5

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

MDM2

Transcript

NM_002392.5

Protein

NP_002383.2:p.(Arg167Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as 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	This is a missense variant (NP_002383.2:p.Arg167Lys). PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice consensus). The generic PVS1 framework (PMC6185798) does not apply to missense substitutions.	pvs1_generic_framework
PS1	Not assessed	No known pathogenic variant with a different nucleotide change at Arg167 was identified in ClinVar or the literature. PS1 cannot be assessed without an established pathogenic comparator at the same amino acid residue.	clinvar
PS2	Not assessed	No de novo data with confirmed paternity and maternity are available for this variant.
PS3	Not assessed	No well-established in vitro or in vivo functional studies were identified for NM_002392.5:c.500G>A. OncoKB classifies the variant as Unknown Oncogenic Effect with no reviewed variant-specific functional evidence.	oncokb
PS4	Not assessed	No case-control or prevalence data are available. The variant is absent from ClinVar with no reported probands.	clinvar
PS5	Not assessed	The variant is absent from ClinVar; no reputable source has issued a pathogenic classification for this variant.	clinvar
PM1	Not met	The variant is not located in a statistically significant mutational hotspot per CancerHotspots. No VCEP-defined functional domain criteria exist for MDM2. Without domain-level evidence or hotspot significance, PM1 is not met.
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue pathogenic missense comparator variants were identified. The automated PM5 candidate search returned no eligible comparators at Arg167.	pm5_candidates
PM6	Not assessed	No de novo reports (with or without confirmed parentage) are available for this variant.
PP1	Not assessed	No co-segregation data are available for this variant.
PP2	Not assessed	Constraint metrics are not available for MDM2 (HCI Prior lookup returned gene not supported). PP2 cannot be assessed without a measure of benign missense constraint.
PP3	Not met	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). The computational evidence does not support a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data are available to support variant-specific phenotyping.
PP5	Not assessed	The variant is absent from ClinVar; no reputable source has issued a pathogenic classification.	clinvar
BA1	Not met	The variant is absent from all gnomAD datasets (v2.1, v4.1, Canada). The allele frequency of 0% is far below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all gnomAD datasets; allele frequency of 0% is far below the non-VCEP BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data are available regarding observation of this variant in healthy adult individuals.
BS3	Not assessed	No well-established in vitro or in vivo functional studies showing no deleterious effect were identified for this variant.
BS4	Not assessed	No non-segregation data are available for this variant.
BP1	Not assessed	BP1 requires a gene where only truncating variants cause disease. MDM2 lacks a well-established germline disease association meeting this threshold. The PVS1 gene context materials cite papers predominantly about other genes (TP63, SAXO6/MDM1, SMARCA4); the two papers mentioning MDM2 (PMID:35549943, PMID:36165233) discuss MDM2 as a drug target or downstream effector, not as a primary germline disease gene with a truncating-only mechanism.	pvs1_gene_context
BP2	Not assessed	No data are available regarding observation of this variant in trans with a known pathogenic variant.
BP4	Met	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 bayesdel spliceai
BP5	Not assessed	No alternative molecular cause has been identified in the case materials.
BP6	Not assessed	The variant is absent from ClinVar; no reputable source has issued a benign classification.	clinvar
BP7	N/A	This is a missense variant (p.Arg167Lys), not a synonymous substitution. BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	BP3 applies to in-frame insertions/deletions; this is a single-nucleotide missense substitution.
PM3	N/A	PM3 applies to recessive disorders; no recessive disease context has been established for MDM2.
PM4	N/A	PM4 applies to non-repeat region in-frame deletions/insertions or stop-loss variants; this is a single-nucleotide missense substitution.

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.