About MDM2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MDM2 c.1270G>A, p.(Glu424Lys)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
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.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
Recorded classification: Uncertain significance
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 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 16 not met · 5 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_002392.5:c.1270G>A (p.Glu424Lys) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population cohorts (PM2).
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).
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).
No criteria match.
Met · 2
PM2 ModerateNM_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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AC=null
- AN=null
- AF=null)
- gnomAD v4.1: absent (AC=null
- gnomAD-Canada v1.0: absent (AC=0
- AN=0
- AF=0.0)
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.08 — predicts benign (<0.5 threshold)
- BayesDel additive score: -0.32377 — predicts benign (negative score)
- SpliceAI max delta: 0.00 — no predicted splice alteration
Sources
Not met · 16 · evaluated, threshold not reached
PS1 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. Details ▾Hide ▴
Evidence considered
- ClinVar has no entries for MDM2 at this residue
- no comparator pathogenic variants available.
Sources
PS2 No de novo observation with confirmed paternity and maternity has been reported for NM_002392.5:c.1270G>A. Details ▾Hide ▴
Evidence considered
- No de novo data available in ClinVar
- literature
- or other evidence sources.
Still missing
- No segregation or family-based studies identified.
PS3 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. Details ▾Hide ▴
Evidence considered
- OncoKB reports no variant-specific reviewed functional evidence
- no variant-specific functional literature identified.
Still missing
- No functional assay data (in vitro or in vivo) for p.Glu424Lys.
Sources
PS4 No case-control or cohort studies comparing variant prevalence in affected vs. unaffected populations are available for NM_002392.5:c.1270G>A. Details ▾Hide ▴
Evidence considered
- No case-control or cohort data identified.
Still missing
- No population-level association data.
PM1 Residue p.Glu424 is not located in a statistically significant mutational hotspot as assessed by CancerHotspots.org. Details ▾Hide ▴
Evidence considered
- CancerHotspots.org reports no significant hotspot at this residue or variant position.
PM6 No assumed de novo observation (without confirmed paternity and maternity) has been reported for NM_002392.5:c.1270G>A. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar
- literature
- or other evidence sources.
Still missing
- No family-based studies available.
PP1 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. Details ▾Hide ▴
Evidence considered
- No family segregation studies identified.
Still missing
- No pedigrees or linkage data.
PP3 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). Details ▾Hide ▴
Evidence considered
- REVEL score: 0.08 (below 0.5 damaging threshold)
- BayesDel score: -0.32377 (negative
- benign-predicting)
- SpliceAI max delta: 0.00 (no predicted splice impact)
Sources
BA1 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%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 and v4.1: variant absent
- frequency = 0.00%
- well below 1% BA1 threshold.
Sources
BS1 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 and v4.1: variant absent
- frequency = 0.00%
- well below 0.3% BS1 threshold.
Sources
BS2 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. Details ▾Hide ▴
Evidence considered
- No evidence of the variant in healthy controls or in trans with known pathogenic variants.
Still missing
- No population or family-based cis/trans phase data.
BS3 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. Details ▾Hide ▴
Evidence considered
- No in vitro or in vivo functional assays for p.Glu424Lys identified.
Still missing
- No experimental functional data for this variant.
BS4 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. Details ▾Hide ▴
Evidence considered
- No family segregation or non-segregation data identified.
Still missing
- No family-based studies.
BP2 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. Details ▾Hide ▴
Evidence considered
- No cis/trans phase data available.
Still missing
- No phasing data with known pathogenic MDM2 variants.
BP5 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. Details ▾Hide ▴
Evidence considered
- No cases with alternative molecular diagnoses have been reported.
Still missing
- No data on alternate molecular diagnoses in carriers.
BP6 NM_002392.5:c.1270G>A is absent from ClinVar. No reputable source has classified this variant as benign or likely benign. Details ▾Hide ▴
Evidence considered
- ClinVar has no entries for this variant
- no benign/likely benign classifications from any submitter.
Sources
Not assessed · 5 · no assessment recorded
PP2 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. Details ▾Hide ▴
Evidence considered
- No HCI prior probability available
- no gnomAD missense constraint metrics provided.
Still missing
- Missense constraint metrics (Z-score
- pLI
- o/e) not available for MDM2.
PP4 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. Details ▾Hide ▴
Evidence considered
- No phenotype or clinical history provided.
Still missing
- Proband phenotype and clinical history not available.
PP5 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. Details ▾Hide ▴
Evidence considered
- PP5 is not a standard ACMG/AMP criterion
- no CSPEC/VCEP to define it for MDM2.
Still missing
- No framework exists to adjudicate PP5 for this gene.
Sources
generic_acmg_combination_rules
BP1 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. Details ▾Hide ▴
Evidence considered
- MDM2 LOF mechanism supported by literature
- however
- established gene-disease validity for an MDM2-specific germline disorder is not confirmed by ClinGen.
Still missing
- No ClinGen gene-disease validity assessment for MDM2
- unclear if truncating variants are primary disease mechanism.
Sources
pvs1_gene_context
PS5 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. Details ▾Hide ▴
Evidence considered
- PS5 is not a standard ACMG/AMP criterion
- no CSPEC/VCEP to define it for MDM2.
Still missing
- No framework exists to adjudicate PS5 for this gene.
Sources
generic_acmg_combination_rules
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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). Details ▾Hide ▴
Evidence considered
- Variant bucket 'other' — missense substitution at codon 424
- not eligible for generic PVS1 null-variant framework.
Sources
PM5 N/ANo 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. Details ▾Hide ▴
Evidence considered
- No pathogenic or likely pathogenic missense variants at codon 424 were found in ClinVar.
Sources
pm5_candidates
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Variant is missense (Glu→Lys)
- BP7 applies only to synonymous variants.
Identifiers
- Gene
- MDM2
- Transcript
- NM_002392.5
- Coding (HGVS c.)
- NM_002392.5:c.1270G>A
- Protein (HGVS p.)
- NP_002383.2:p.(Glu424Lys)
- GRCh38
- chr12:68839625 G>A
- GRCh37
- chr12:69233405 G>A
Gene diagram
Every interpreted variant in MDM2, mapped onto the exon structure of NM_002392.5. Select a row to find it on the plot.
MDM2NM_002392.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in MDM2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.080
- BayesDel
- -0.324
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.08 — predicts benign (<0.5 threshold)
- BayesDel additive score: -0.32377 — predicts benign (negative score)
- SpliceAI max delta: 0.00 — no predicted splice alteration
Sources
PP3 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). Details ▾Hide ▴
Evidence considered
- REVEL score: 0.08 (below 0.5 damaging threshold)
- BayesDel score: -0.32377 (negative
- benign-predicting)
- SpliceAI max delta: 0.00 (no predicted splice impact)
Sources
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Variant is missense (Glu→Lys)
- BP7 applies only to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.08. BayesDel score = -0.32377.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_002392.5%3Ac.1270G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-69233405-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-68839625-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-68839625-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002392.5%3Ac.1270…
- OncoKB ↗www.oncokb.org/gene/MDM2/E424K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MDM2+c.1270G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.08. BayesDel score = -0.32377.
Functional
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.