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 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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