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.1 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.2 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.3 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.4
MDM2
Final classification
Likely Pathogenic
MDM2 c.918+1G>C · p.?
MDM2
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.
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.
Classification rationale
PVS1PM2
Likely Pathogenic
MDM2 c.918+1G>C
PVS1 + PM2
→
Likely Pathogenic
1
pvs1_generic_framework ↗pvs1_gene_contextspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_002392.5 · variants mapped to exon structure
MDM2
NM_002392.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
review
Pathogenic
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.
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
✓
PM2
moderate
Pathogenic
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.
Absent in gnomAD v2.1gnomAD v4.1: 2/1595
Assessed · not applied
Pathogenic
PS2
No de novo occurrence of NM_002392.5:c.918+1G>C has been reported in any patient with a consistent phenotype.
PS3
No functional assays (minigene splicing, RNA analysis, or protein studies) have been performed for this variant.
PS4
No case-control studies have demonstrated statistically significant enrichment of this variant in affected individuals.
PM1
No evidence that this splice junction constitutes a recognized mutational hotspot or critical functional domain in MDM2.
PM6
No de novo event (without confirmation of paternity and maternity) has been reported for this variant.
PP1
No co-segregation data are available for this variant in affected families.
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.
PP4
No patient phenotype data are available to assess phenotype specificity for this variant.
PP5
No reputable source (ClinVar expert panel or clinical diagnostic laboratory) has classified this variant as pathogenic.
Benign
BA1
The variant frequency in gnomAD v4.1 (MAF=0.00013%) is far below the BA1 threshold of >1%.
BS1
The variant frequency in gnomAD v4.1 (MAF=0.00013%) is far below the BS1 threshold of >0.3%.
BS2
No evidence that this variant has been observed in healthy adults with complete penetrance data.
BS3
No functional studies demonstrating normal splicing or protein function have been performed for this variant.
BS4
No family studies demonstrating lack of co-segregation with disease are available for this variant.
BP2
No observation of this variant in cis with a known pathogenic MDM2 variant has been reported.
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.
BP5
No case has been identified in which this variant is found in an individual with an alternate molecular cause for disease.
BP6
No reputable source has classified this variant as benign.
N/A · 5
PS1 · PM5 · PP2 · BP1 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
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.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00013%
· 2 / 1,595,872
0 hom · FAF 2.9e-05%
0 hom · FAF 2.9e-05%
European (non-Finnish) 2 / 1,164,170 |
0.00017% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = -0.0690792.
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links