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MDM2c.918+1G>CLikely pathogenic
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Variant interpretation report

MDM2 c.918+1G>C, p.?

NM_002392.5:c.918+1G>C NP_002383.2:p.? View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

NM_002392.5:c.918+1G>C is a canonical +1 splice donor variant in intron 10 of MDM2. SpliceAI predicts loss of the native donor (DS_DL=0.99) and activation of a cryptic acceptor (DS_AL=0.99), consistent with aberrant splicing. MDM2 germline loss-of-function is supported as a disease mechanism per ClinGen SVI PVS1 gene-level review (PMC6185798). Under the generic PVS1 decision framework, canonical splice variants in genes with established LoF disease mechanism receive full PVS1 strength.

PM2Moderate
PM2 · moderate

This variant is absent from gnomAD v2.1 and extremely rare in gnomAD v4.1 (2/1,595,872 alleles; MAF=0.00013%), well below the 0.1% PM2 threshold. It is also absent from gnomAD-Canada.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.

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
0.990 maximum delta

Recorded SpliceAI maximum delta score: 0.990. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗
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 · 18 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_002392.5:c.918+1G>C is a canonical +1 splice donor variant in intron 10 of MDM2, predicted to abolish the native splice donor site (SpliceAI DS_DL=0.99). PVS1 is applied at very strong strength under the ClinGen SVI generic PVS1 framework (PMC6185798), as MDM2 germline loss-of-function is supported as a disease mechanism.

The variant is absent from gnomAD v2.1, absent from gnomAD-Canada, and extremely rare in gnomAD v4.1 (2/1,595,872 alleles, MAF=0.00013%), meeting PM2 at moderate strength.

No other pathogenic or benign criteria were met. The variant is absent from ClinVar, has no published functional studies, no case-control data, and no reported de novo or segregation evidence.

Applying generic ACMG/AMP 2015 final classification rules (Richards et al., PMID:25741868): one Very Strong criterion (PVS1) plus one Moderate criterion (PM2) yields a classification of Likely Pathogenic.

Met · 2

PVS1 Very strongNM_002392.5:c.918+1G>C is a canonical +1 splice donor variant in intron 10 of MDM2. SpliceAI predicts loss of the native donor (DS_DL=0.99) and activation of a cryptic acceptor (DS_AL=0.99), consistent with aberrant splicing. MDM2 germline loss-of-function is supported as a disease mechanism per ClinGen SVI PVS1 gene-level review (PMC6185798). Under the generic PVS1 decision framework, canonical splice variants in genes with established LoF disease mechanism receive full PVS1 strength. Details ▾Hide ▴
Evidence considered
  • Canonical +1 splice donor variant (intron 10 of NM_002392.5)
  • SpliceAI predicts donor loss (DS_DL=0.99) and acceptor loss (DS_AL=0.99)
  • MDM2 germline LoF supported as disease mechanism per targeted literature review
Still missing
  • No functional RNA studies confirming aberrant splicing for this specific variant
  • No CSPEC/VCEP for MDM2 to provide gene-specific PVS1 guidance
  • MDM2 is a proto-oncogene where overexpression is oncogenic
  • germline LoF disease mechanism is inferred from literature rather than established by a formal ClinGen expert panel
Sources
pvs1_generic_framework ↗pvs1_gene_contextspliceai ↗
PM2 ModerateThis variant is absent from gnomAD v2.1 and extremely rare in gnomAD v4.1 (2/1,595,872 alleles; MAF=0.00013%), well below the 0.1% PM2 threshold. It is also absent from gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • Absent in gnomAD v2.1
  • gnomAD v4.1: 2/1
  • 595
  • 872 alleles (AF=1.25e-6
  • MAF=0.00013%)
  • homozygotes=0
  • all observed in European (non-Finnish) population
  • Absent from gnomAD-Canada v1.0
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 18 · evaluated, threshold not reached

PS2 No de novo occurrence of NM_002392.5:c.918+1G>C has been reported in any patient with a consistent phenotype. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in ClinVar
  • literature
  • or public databases
Still missing
  • No case reports or parental testing data available
PS3 No functional assays (minigene splicing, RNA analysis, or protein studies) have been performed for this variant. Details ▾Hide ▴
Evidence considered
  • No functional studies identified for NM_002392.5:c.918+1G>C
Still missing
  • Absence of experimental functional data for this specific variant
PS4 No case-control studies have demonstrated statistically significant enrichment of this variant in affected individuals. The variant is extremely rare in population databases (gnomAD v4.1 AF=1.25e-6) and absent from ClinVar, precluding statistical comparison. Details ▾Hide ▴
Evidence considered
  • Variant frequency in gnomAD v4.1 is 1.25e-6
  • precluding case-control power
Still missing
  • No case-control or cohort data available
Sources
gnomad_v4 ↗
PM1 No evidence that this splice junction constitutes a recognized mutational hotspot or critical functional domain in MDM2. PM1 under generic ACMG/AMP is applied to protein-level domain hotspots, not splice consensus sequences, and no VCEP has designated this region as a hotspot. Details ▾Hide ▴
Evidence considered
  • No mutational hotspot or critical domain designation for this splice junction in MDM2
Still missing
  • No VCEP-defined mutational hotspot map for MDM2
PM6 No de novo event (without confirmation of paternity and maternity) has been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports in ClinVar or literature
Still missing
  • No de novo observations available
PP1 No co-segregation data are available for this variant in affected families. Details ▾Hide ▴
Evidence considered
  • No family studies or segregation data identified
Still missing
  • No pedigree or co-segregation data
PP3 Per ClinGen SVI PVS1 recommendations (PMC6185798), in silico splice prediction evidence should not be double-counted when PVS1 is applied for the same splice-effect mechanism. SpliceAI max delta=0.99 strongly predicts aberrant splicing, but this evidence is already captured by PVS1. BayesDel score (-0.069) is neutral and does not independently support pathogenicity. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.99 (not double-counted per PVS1 framework)
  • BayesDel=-0.069 (neutral
  • below pathogenic threshold)
Sources
spliceai ↗bayesdel
PP4 No patient phenotype data are available to assess phenotype specificity for this variant. Details ▾Hide ▴
Evidence considered
  • No clinical phenotype information available
Still missing
  • No patient phenotype data
PP5 No reputable source (ClinVar expert panel or clinical diagnostic laboratory) has classified this variant as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
Still missing
  • No ClinVar submissions from any source
Sources
clinvar ↗
BA1 The variant frequency in gnomAD v4.1 (MAF=0.00013%) is far below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 MAF=0.00013%
  • far below 1% BA1 cutoff
Sources
gnomad_v4 ↗
BS1 The variant frequency in gnomAD v4.1 (MAF=0.00013%) is far below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 MAF=0.00013%
  • far below 0.3% BS1 cutoff
Sources
gnomad_v4 ↗
BS2 No evidence that this variant has been observed in healthy adults with complete penetrance data. The two gnomAD v4.1 observations are population-based and lack accompanying individual phenotype information. Details ▾Hide ▴
Evidence considered
  • gnomAD observations are population-based with no individual phenotype data
Still missing
  • No observation in confirmed healthy adults with full penetrance data
BS3 No functional studies demonstrating normal splicing or protein function have been performed for this variant. Details ▾Hide ▴
Evidence considered
  • No functional studies available
Still missing
  • No experimental evidence of normal function
BS4 No family studies demonstrating lack of co-segregation with disease are available for this variant. Details ▾Hide ▴
Evidence considered
  • No non-segregation data
Still missing
  • No non-segregation evidence
BP2 No observation of this variant in cis with a known pathogenic MDM2 variant has been reported. Details ▾Hide ▴
Evidence considered
  • No phasing data available
Still missing
  • No cis-configuration data with pathogenic variants
BP4 SpliceAI predicts a deleterious splice effect (max delta=0.99, DS_DL=0.99, DS_AL=0.99), which is inconsistent with a benign interpretation. BayesDel (-0.069) alone is insufficient to support BP4 when a splice-specific predictor strongly indicates aberrant splicing for a splice variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI predicts damaging splice effect (max delta=0.99)
  • BayesDel=-0.069 cannot override splice-specific prediction for a canonical splice variant
Sources
spliceai ↗bayesdel
BP5 No case has been identified in which this variant is found in an individual with an alternate molecular cause for disease. Details ▾Hide ▴
Evidence considered
  • No clinical cases with alternate molecular diagnoses
Still missing
  • No cases with alternate molecular basis
BP6 No reputable source has classified this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
Still missing
  • No benign classifications from any source
Sources
clinvar ↗
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies when a different nucleotide change at the same position has been established as pathogenic. This is a splice site variant with no applicable same-position comparator. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 requires a different pathogenic missense change at the same amino acid residue. This is a canonical splice site variant with no applicable amino acid residue context; PM5 semantics cannot be applied. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies exclusively to missense variants in genes with a low rate of benign missense variation. This is a canonical splice site variant, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where a truncating mechanism is the primary cause of disease. This is a canonical splice site variant, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a canonical +1 splice donor variant predicted to alter splicing, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/ANo ClinVar submissions exist for this variant; PS5 requires a reputable source to have classified the variant as pathogenic. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
MDM2
Transcript
NM_002392.5
Coding (HGVS c.)
NM_002392.5:c.918+1G>C
Protein (HGVS p.)
NP_002383.2:p.?
GRCh38
chr12:68836750 G>C
GRCh37
chr12:69230530 G>C

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 2 / 1,595,872 alleles AF 1.25e-06 · 0 homozygotes · FAF 2.9e-07
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v4.1

AF 1.3e-06 · 2 / 1,595,872 alleles · 0 hom · FAF 2.9e-07
European (non-Finnish)2 / 1,164,170 1.7e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.25323e-06; MAF= 0.00013%, 2/1595872 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.71796e-06; MAF= 0.00017%, 2/1164170 alleles, homozygotes = 0); grpmax FAF= 2.9e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -78 bp
0.990
SpliceAI acceptor gainat +43 bp
0.000
SpliceAI donor lossat -1 bp
0.990
SpliceAI donor gainat +346 bp
0.000
Pangolin splice lossmagnitude shown
-0.890
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
-0.069

How the predictions were used

PP3 Per ClinGen SVI PVS1 recommendations (PMC6185798), in silico splice prediction evidence should not be double-counted when PVS1 is applied for the same splice-effect mechanism. SpliceAI max delta=0.99 strongly predicts aberrant splicing, but this evidence is already captured by PVS1. BayesDel score (-0.069) is neutral and does not independently support pathogenicity. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.99 (not double-counted per PVS1 framework)
  • BayesDel=-0.069 (neutral
  • below pathogenic threshold)
Sources
spliceai ↗bayesdel
BP4 SpliceAI predicts a deleterious splice effect (max delta=0.99, DS_DL=0.99, DS_AL=0.99), which is inconsistent with a benign interpretation. BayesDel (-0.069) alone is insufficient to support BP4 when a splice-specific predictor strongly indicates aberrant splicing for a splice variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI predicts damaging splice effect (max delta=0.99)
  • BayesDel=-0.069 cannot override splice-specific prediction for a canonical splice variant
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a canonical +1 splice donor variant predicted to alter splicing, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = -0.0690792.

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 2 / 1,595,872 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.990 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC 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

This variant is present in gnomAD v4.1 (AF= 1.25323e-06; MAF= 0.00013%, 2/1595872 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.71796e-06; MAF= 0.00017%, 2/1164170 alleles, homozygotes = 0); grpmax FAF= 2.9e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = -0.0690792.

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).