Variant classification summary

NM_002392.5:c.1270G>A

MDM2 · NP_002383.2:p.(Glu424Lys) · NM_002392.5

GRCh37: chr12:69233405 G>A · GRCh38: chr12:68839625 G>A

Gene: MDM2 Transcript: NM_002392.5

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

MDM2

Transcript

NM_002392.5

Protein

NP_002383.2:p.(Glu424Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_002392.5:c.1270G>A (p.Glu424Lys) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population cohorts (PM2).

2

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).

3

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).

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.1270G>A is a missense variant (NP_002383.2:p.(Glu424Lys)). It does not fall into the ClinGen SVI PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus. PVS1 is not applicable to missense substitutions under the generic PVS1 framework (PMC6185798).	pvs1_generic_framework
PS1	Not met	No pathogenic or likely pathogenic variant at the same amino acid residue (NP_002383.2:p.Glu424) has been identified in ClinVar. PS1 requires a previously established pathogenic missense change at the same codon.	clinvar
PS2	Not met	No de novo observation with confirmed paternity and maternity has been reported for NM_002392.5:c.1270G>A.
PS3	Not met	No well-established functional studies demonstrating a damaging effect have been identified for NM_002392.5:c.1270G>A. OncoKB classifies this variant as having unknown oncogenic effect.	oncokb
PS4	Not met	No case-control or cohort studies comparing variant prevalence in affected vs. unaffected populations are available for NM_002392.5:c.1270G>A.
PS5	Not assessed	PS5 is not a recognized criterion in the standard ACMG/AMP 2015 classification framework (Richards et al., PMID:25741868). No gene-specific VCEP/CSPEC framework defining a PS5 criterion is available for MDM2.	generic_acmg_combination_rules
PM1	Not met	Residue p.Glu424 is not located in a statistically significant mutational hotspot as assessed by CancerHotspots.org.
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variants with established pathogenicity were identified. PM5 candidate harvesting returned zero candidates; automatic candidate search was not triggered due to inability to confirm classic same-residue PM5 semantics.	pm5_candidates
PM6	Not met	No assumed de novo observation (without confirmed paternity and maternity) has been reported for NM_002392.5:c.1270G>A.
PP1	Not met	No co-segregation data are available for NM_002392.5:c.1270G>A. PP1 requires evidence that the variant co-segregates with disease in multiple affected family members.
PP2	Not assessed	PP2 requires a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease. HCI prior data are not available for MDM2, and gnomAD missense constraint metrics (Z-score, pLI, missense o/e) were not provided in the evidence packet. Insufficient data to adjudicate PP2.
PP3	Not met	Multiple lines of in silico computational evidence do not support a deleterious effect. REVEL score is 0.08 (well below the 0.5 threshold for pathogenic prediction), BayesDel additive score is -0.32377 (negative, predicting benign), and SpliceAI predicts no splicing impact (max delta score = 0.00).	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or clinical history data are available for this variant. PP4 cannot be adjudicated without information about the proband's clinical presentation in relation to MDM2-associated disease.
PP5	Not assessed	PP5 is not a recognized criterion in the standard ACMG/AMP 2015 classification framework (Richards et al., PMID:25741868). No gene-specific VCEP/CSPEC framework defining a PP5 criterion is available for MDM2.	generic_acmg_combination_rules
BA1	Not met	NM_002392.5:c.1270G>A is absent from all gnomAD population cohorts. Allele frequency of 0.00% does not meet the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	NM_002392.5:c.1270G>A is absent from all gnomAD population cohorts. Allele frequency of 0.00% does not meet the BS1 threshold of >0.3% for a gene without an expert panel framework.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available regarding observation of NM_002392.5:c.1270G>A in healthy adult individuals. BS2 requires that the variant be observed in a homozygous or hemizygous state, or in trans with a known pathogenic variant, in a healthy individual with a fully penetrant disorder.
BS3	Not met	No well-established functional studies demonstrating no deleterious effect have been identified for NM_002392.5:c.1270G>A. While in silico predictors (REVEL, BayesDel) favor a benign interpretation, these do not constitute functional assay evidence.
BS4	Not met	No data are available regarding lack of co-segregation with disease for NM_002392.5:c.1270G>A. BS4 requires evidence that the variant does not segregate with disease in affected families.
BP1	Not assessed	BP1 requires a missense variant in a gene for which primarily truncating variants are known to cause disease. While loss-of-function is supported as a disease mechanism for MDM2 (PVS1 gene gate: eligible), the evidence for a specific inherited MDM2 germline disorder is based on targeted literature review rather than an established ClinGen gene-disease validity assessment. It is unclear whether truncating variants are the primary or exclusive disease mechanism for MDM2. Insufficient evidence to apply BP1.	pvs1_gene_context
BP2	Not met	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.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No data are available regarding observation of NM_002392.5:c.1270G>A in a case with an alternative molecular basis for disease. BP5 requires that the variant be found in a case with a clearly established alternate genetic cause.
BP6	Not met	NM_002392.5:c.1270G>A is absent from ClinVar. No reputable source has classified this variant as benign or likely benign.	clinvar
BP7	N/A	NM_002392.5:c.1270G>A is a missense variant (p.Glu424Lys), not a synonymous variant. BP7 is only applicable to synonymous variants with no predicted splice impact.

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