NM_002392.5:c.1036G>A

MDM2 · NP_002383.2:p.(Glu346Lys) · NM_002392.5

GRCh37: chr12:69233171 G>A · GRCh38: chr12:68839391 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.(Glu346Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

The variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).

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).

The variant is absent from ClinVar with no classifications, no functional studies, no case reports, and no segregation data available.

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).

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	NM_002392.5:c.1036G>A is a missense variant (p.Glu346Lys) in MDM2 exon 11. It does not fall into the ClinGen SVI PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No known pathogenic variant with the same amino acid change (p.Glu346Lys) has been identified in ClinVar or the literature for MDM2.	clinvar
PS2	Not met	No de novo observation with confirmed paternity and maternity has been reported for NM_002392.5:c.1036G>A.
PS3	Not met	No well-established functional studies demonstrate a damaging effect for NM_002392.5:c.1036G>A. OncoKB reports an unknown oncogenic effect with no variant-specific functional evidence curated.	oncokb
PS4	Not met	The variant is absent from ClinVar and no case-control studies comparing prevalence in affected individuals versus controls are available.	clinvar
PS5	Not met	No reputable source (clinical diagnostic laboratory, expert panel, or curated database) classifies NM_002392.5:c.1036G>A as pathogenic. The variant is absent from ClinVar.	clinvar
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same residue (p.Glu346) has been identified in ClinVar to serve as a PM5 comparator. Automated candidate harvesting returned zero same-residue candidates.	pm5_candidates clinvar
PM6	Not met	No de novo observation (with or without confirmed parentage) has been reported for NM_002392.5:c.1036G>A.
PP1	Not met	No cosegregation data are available for NM_002392.5:c.1036G>A.
PP2	Not met	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. No HCI prior score is available (gene not supported by HCI), and no ClinGen gene-disease validity curation exists for MDM2 in a germline context.
PP3	Not met	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).	revel bayesdel spliceai
PP4	Not met	No clinical phenotype or family history data are available for individuals carrying NM_002392.5:c.1036G>A.
PP5	Not met	No reputable source (clinical laboratory, expert panel, or database) classifies NM_002392.5:c.1036G>A as pathogenic. The variant is absent from ClinVar.	clinvar
BA1	Not met	NM_002392.5:c.1036G>A is absent from gnomAD v2.1 and v4.1. It does not meet the BA1 allele frequency threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	NM_002392.5:c.1036G>A is absent from gnomAD v2.1 and v4.1. It does not meet the BS1 allele frequency threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No observation of NM_002392.5:c.1036G>A in healthy adult individuals has been reported in available data sources. The variant is absent from all population databases, precluding assessment of its presence in healthy controls.
BS3	Not met	No well-established functional studies demonstrating a benign effect exist for NM_002392.5:c.1036G>A. While in silico predictions are benign-leaning, these are addressed under BP4 and do not constitute BS3-level experimental evidence.
BS4	Not met	No segregation data are available to assess lack of cosegregation with disease for NM_002392.5:c.1036G>A.
BP1	Not met	BP1 requires a missense variant in a gene for which primarily truncating variants are known to cause disease. MDM2 has no well-established germline disease association where truncating variants are the primary pathogenic mechanism. The PVS1 gene context literature review identified MDM2-related therapeutic studies (Nutlin-3 in fragile X mouse model, MDM2 inhibition in ADPKD) but no germline MDM2 truncating variant disease spectrum.	pvs1_gene_context
BP2	Not met	No observation of NM_002392.5:c.1036G>A in trans with a pathogenic variant in a fully penetrant dominant gene has been reported.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No alternative molecular basis for disease has been identified in a case with NM_002392.5:c.1036G>A. No clinical case data are available.
BP6	Not met	No reputable source classifies NM_002392.5:c.1036G>A as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	NM_002392.5:c.1036G>A is a missense variant (p.Glu346Lys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	Substitution variant; BP3 applies to in-frame indels in repeat regions.
PM3	N/A	No recessive disorder context; PM3 applies to variants detected in trans with a pathogenic variant in recessive disorders.
PM4	N/A	Substitution variant; PM4 applies to protein-length-altering indels or nonsense variants in non-repeat regions.

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.