About MDM2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MDM2 c.500G>A, p.(Arg167Lys)
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
PM2Supporting
PM2 · supporting
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%.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
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.
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.
29 criteria with recorded statuses: 2 met · 4 not met · 17 not assessed · 6 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.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.
No criteria match.
Met · 2
PM2 SupportingThis 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%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AF <0.1%)
- gnomAD v4.1: absent (AF <0.1%)
- gnomAD-Canada v1.0: absent (AF=0.0)
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.144 (benign/tolerated range)
- BayesDel: -0.333371 (tolerated)
- SpliceAI max delta: 0.00 (no predicted splice impact)
Sources
Not met · 4 · evaluated, threshold not reached
PM1 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. Details ▾Hide ▴
Evidence considered
- CancerHotspots: residue not significant
- exact variant not listed.
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.144 (below 0.5 damaging threshold)
- BayesDel: -0.333371 (negative
- tolerated prediction)
- SpliceAI max delta: 0.00 (no splice impact)
Sources
BA1 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%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AF=0%)
- gnomAD v4.1: absent (AF=0%)
- gnomAD-Canada: absent (AF=0.0)
Sources
BS1 The variant is absent from all gnomAD datasets; allele frequency of 0% is far below the non-VCEP BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AF=0%)
- gnomAD v4.1: absent (AF=0%)
- gnomAD-Canada: absent (AF=0.0)
Sources
Not assessed · 17 · no assessment recorded
PS1 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. Details ▾Hide ▴
Evidence considered
- ClinVar search returned no entries for this variant or any variant at Arg167.
Still missing
- No ClinVar entries for any variant at Arg167.
Sources
PS2 No de novo data with confirmed paternity and maternity are available for this variant. Details ▾Hide ▴
Evidence considered
- No literature or clinical data reporting de novo occurrence.
Still missing
- No de novo reports identified.
PS3 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. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence curated.
Still missing
- No functional data available.
Sources
PS4 No case-control or prevalence data are available. The variant is absent from ClinVar with no reported probands. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no affected vs. control data.
Still missing
- No prevalence or case-control data available.
Sources
PM6 No de novo reports (with or without confirmed parentage) are available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo observations identified in any source.
Still missing
- No de novo data available.
PP1 No co-segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
- No family studies or segregation data identified.
Still missing
- No co-segregation data available.
PP2 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. Details ▾Hide ▴
Evidence considered
- HCI Prior: gene not supported
- no constraint data available.
Still missing
- No missense constraint metrics available for MDM2.
PP4 No patient phenotype or family history data are available to support variant-specific phenotyping. Details ▾Hide ▴
Evidence considered
- No phenotype or clinical data available.
Still missing
- No phenotype data available.
PP5 The variant is absent from ClinVar; no reputable source has issued a pathogenic classification. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar.
Still missing
- No ClinVar classification available.
Sources
BS2 No data are available regarding observation of this variant in healthy adult individuals. Details ▾Hide ▴
Evidence considered
- No healthy adult observation data available.
Still missing
- No observation in healthy controls reported.
BS3 No well-established in vitro or in vivo functional studies showing no deleterious effect were identified for this variant. Details ▾Hide ▴
Evidence considered
- No functional studies showing benign effect identified.
Still missing
- No functional data available.
BS4 No non-segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No non-segregation data available.
BP1 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. Details ▾Hide ▴
Evidence considered
- No established germline disease gene with truncating-only mechanism for MDM2.
Still missing
- MDM2 lacks well-established germline disease association meeting BP1 requirements.
Sources
pvs1_gene_context
BP2 No data are available regarding observation of this variant in trans with a known pathogenic variant. Details ▾Hide ▴
Evidence considered
- No trans-observation data available.
Still missing
- No data on observations in trans.
BP5 No alternative molecular cause has been identified in the case materials. Details ▾Hide ▴
Evidence considered
- No alternative molecular cause reported.
Still missing
- No data on alternative molecular basis.
BP6 The variant is absent from ClinVar; no reputable source has issued a benign classification. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar.
Still missing
- No ClinVar classification available.
Sources
PS5 The variant is absent from ClinVar; no reputable source has issued a pathogenic classification for this variant. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no classification by any submitter.
Still missing
- No ClinVar entry or expert panel classification.
Sources
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis 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. Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null variant eligible for PVS1 assessment.
Sources
PM3 N/APM3 applies to recessive disorders; no recessive disease context has been established for MDM2. Details ▾Hide ▴
Evidence considered
- No recessive disorder context for MDM2.
PM4 N/APM4 applies to non-repeat region in-frame deletions/insertions or stop-loss variants; this is a single-nucleotide missense substitution. Details ▾Hide ▴
Evidence considered
- Missense variant
- not an in-frame indel or stop-loss.
PM5 N/ANo same-residue pathogenic missense comparator variants were identified. The automated PM5 candidate search returned no eligible comparators at Arg167. Details ▾Hide ▴
Evidence considered
- Zero same-residue comparator candidates identified at Arg167.
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame insertions/deletions; this is a single-nucleotide missense substitution. Details ▾Hide ▴
Evidence considered
- Missense variant
- not an in-frame indel.
BP7 N/AThis is a missense variant (p.Arg167Lys), not a synonymous substitution. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous substitutions.
Identifiers
- Gene
- MDM2
- Transcript
- NM_002392.5
- Coding (HGVS c.)
- NM_002392.5:c.500G>A
- Protein (HGVS p.)
- NP_002383.2:p.(Arg167Lys)
- GRCh38
- chr12:68824628 G>A
- GRCh37
- chr12:69218408 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
- 0.144
- BayesDel
- -0.333
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.144 (benign/tolerated range)
- BayesDel: -0.333371 (tolerated)
- SpliceAI max delta: 0.00 (no predicted splice impact)
Sources
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.144 (below 0.5 damaging threshold)
- BayesDel: -0.333371 (negative
- tolerated prediction)
- SpliceAI max delta: 0.00 (no splice impact)
Sources
BP7 N/AThis is a missense variant (p.Arg167Lys), not a synonymous substitution. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous substitutions.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.144. BayesDel score = -0.333371.
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.500G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-69218408-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-68824628-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-68824628-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002392.5%3Ac.500G…
- OncoKB ↗www.oncokb.org/gene/MDM2/R167K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MDM2+c.500G%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 = 0.144. BayesDel score = -0.333371.
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.