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MDM2c.1036G>AUncertain significance
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Variant interpretation report

MDM2 c.1036G>A, p.(Glu346Lys)

NM_002392.5:c.1036G>A NP_002383.2:p.(Glu346Lys) View identifiers
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.

About MDM2

No gene-level summary was recorded for this case.

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
PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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.

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 supporting, BP4 supporting benign; combination = 1 supporting + 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.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

Met · 2

PM2 SupportingNM_002392.5:c.1036G>A is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), supporting rarity in the general population. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (search status: absent).
  • Absent from gnomAD v4.1 (search status: absent).
  • Absent from gnomAD-Canada v1.0 (search status: absent).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.037 (strongly benign-leaning).
  • BayesDel: -0.61515 (benign prediction).
  • SpliceAI: max delta 0.00 (no splicing impact predicted).
Sources
revelbayesdelspliceai ↗

Not met · 22 · evaluated, threshold not reached

PS1 No known pathogenic variant with the same amino acid change (p.Glu346Lys) has been identified in ClinVar or the literature for MDM2. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no pathogenic comparator with the same amino acid change identified.
Still missing
  • No curated database of pathogenic MDM2 missense variants available.
Sources
clinvar ↗
PS2 No de novo observation with confirmed paternity and maternity has been reported for NM_002392.5:c.1036G>A. Details ▾Hide ▴
Evidence considered
  • No de novo data available in ClinVar or literature.
Still missing
  • No family-based sequencing data available.
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no variant-specific functional studies identified.
Still missing
  • No experimental functional characterization of p.E346K has been performed.
Sources
oncokb ↗
PS4 The variant is absent from ClinVar and no case-control studies comparing prevalence in affected individuals versus controls are available. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no case-control data available.
Still missing
  • No cohort or case-control studies for MDM2 p.E346K.
Sources
clinvar ↗
PM1 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. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots reports residue E346 as not significant
  • no domain-level enrichment data available.
Still missing
  • No MDM2-specific domain-level constraint or missense enrichment data available.
PM5 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. Details ▾Hide ▴
Evidence considered
  • No pathogenic ClinVar entries at MDM2 residue E346 identified.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation (with or without confirmed parentage) has been reported for NM_002392.5:c.1036G>A. Details ▾Hide ▴
Evidence considered
  • No de novo data available.
Still missing
  • No family-based sequencing data available.
PP1 No cosegregation data are available for NM_002392.5:c.1036G>A. Details ▾Hide ▴
Evidence considered
  • No family studies or cosegregation analysis reported.
Still missing
  • No family-based sequencing or linkage data.
PP2 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. Details ▾Hide ▴
Evidence considered
  • MDM2 lacks established germline disease association with missense constraint
  • HCI prior not available for this gene.
Still missing
  • No ClinGen gene-disease validity curation for MDM2 germline disorders.
PP3 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). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.037 (benign-leaning
  • below 0.5 threshold).
  • BayesDel: -0.61515 (benign prediction).
  • SpliceAI max delta: 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
PP4 No clinical phenotype or family history data are available for individuals carrying NM_002392.5:c.1036G>A. Details ▾Hide ▴
Evidence considered
  • No clinical phenotype data available.
Still missing
  • No proband phenotype or clinical history available.
PP5 No reputable source (clinical laboratory, expert panel, or database) classifies NM_002392.5:c.1036G>A as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no pathogenic classification from any submitter.
Sources
clinvar ↗
BA1 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%. Details ▾Hide ▴
Evidence considered
  • Variant absent from gnomAD
  • frequency is 0%
  • well below the 1% BA1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 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%. Details ▾Hide ▴
Evidence considered
  • Variant absent from gnomAD
  • frequency is 0%
  • well below the 0.3% BS1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 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. Details ▾Hide ▴
Evidence considered
  • No observation in healthy adults reported.
Still missing
  • No phenotype-linked cohort data available.
BS3 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. Details ▾Hide ▴
Evidence considered
  • No experimental functional studies available for p.E346K.
Still missing
  • No in vitro or in vivo functional characterization of p.E346K.
BS4 No segregation data are available to assess lack of cosegregation with disease for NM_002392.5:c.1036G>A. Details ▾Hide ▴
Evidence considered
  • No family segregation data available.
Still missing
  • No family-based studies available.
BP1 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. Details ▾Hide ▴
Evidence considered
  • No established germline MDM2 disease with truncating variants as primary mechanism.
Still missing
  • No ClinGen gene-disease validity for germline MDM2 disease.
Sources
pvs1_gene_context
BP2 No observation of NM_002392.5:c.1036G>A in trans with a pathogenic variant in a fully penetrant dominant gene has been reported. Details ▾Hide ▴
Evidence considered
  • No trans configuration data available.
BP5 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. Details ▾Hide ▴
Evidence considered
  • No alternative molecular diagnosis data available.
Still missing
  • No clinical case data available for this variant.
BP6 No reputable source classifies NM_002392.5:c.1036G>A as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no benign classification from any submitter.
Sources
clinvar ↗
PS5 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. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no submitter or expert panel classification available.
Sources
clinvar ↗
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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). Details ▾Hide ▴
Evidence considered
  • Missense variant p.E346K is not a null variant eligible for PVS1.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/ANo recessive disorder context; PM3 applies to variants detected in trans with a pathogenic variant in recessive disorders. Details ▾Hide ▴

No further detail was recorded.

PM4 N/ASubstitution variant; PM4 applies to protein-length-altering indels or nonsense variants in non-repeat regions. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ASubstitution variant; BP3 applies to in-frame indels in repeat regions. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 is reserved for synonymous variants.

Identifiers

Gene
MDM2
Transcript
NM_002392.5
Coding (HGVS c.)
NM_002392.5:c.1036G>A
Protein (HGVS p.)
NP_002383.2:p.(Glu346Lys)
GRCh38
chr12:68839391 G>A
GRCh37
chr12:69233171 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…
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

Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.037
BayesDel
-0.615

How the predictions were used

BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.037 (strongly benign-leaning).
  • BayesDel: -0.61515 (benign prediction).
  • SpliceAI: max delta 0.00 (no splicing impact predicted).
Sources
revelbayesdelspliceai ↗
PP3 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). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.037 (benign-leaning
  • below 0.5 threshold).
  • BayesDel: -0.61515 (benign prediction).
  • SpliceAI max delta: 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 is reserved for synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.037. BayesDel score = -0.61515.

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

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 = 0.037. BayesDel score = -0.61515.

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.