NM_002392.5:c.918+1G>C

MDM2 · NP_002383.2:p.? · NM_002392.5

GRCh37: chr12:69230530 G>C · GRCh38: chr12:68836750 G>C

Gene: MDM2 Transcript: NM_002392.5

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

MDM2

Transcript

NM_002392.5

Protein

NP_002383.2:p.?

gnomAD AF

1.2532333420224177e-06 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	pvs1_generic_framework pvs1_gene_context spliceai
PS1	N/A	PS1 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.
PS2	Not met	No de novo occurrence of NM_002392.5:c.918+1G>C has been reported in any patient with a consistent phenotype.
PS3	Not met	No functional assays (minigene splicing, RNA analysis, or protein studies) have been performed for this variant.
PS4	Not met	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.	gnomad_v4
PS5	N/A	No ClinVar submissions exist for this variant; PS5 requires a reputable source to have classified the variant as pathogenic.
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 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.
PM6	Not met	No de novo event (without confirmation of paternity and maternity) has been reported for this variant.
PP1	Not met	No co-segregation data are available for this variant in affected families.
PP2	N/A	PP2 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.
PP3	Not met	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.	spliceai bayesdel
PP4	Not met	No patient phenotype data are available to assess phenotype specificity for this variant.
PP5	Not met	No reputable source (ClinVar expert panel or clinical diagnostic laboratory) has classified this variant as pathogenic. The variant is absent from ClinVar.	clinvar
BA1	Not met	The variant frequency in gnomAD v4.1 (MAF=0.00013%) is far below the BA1 threshold of >1%.	gnomad_v4
BS1	Not met	The variant frequency in gnomAD v4.1 (MAF=0.00013%) is far below the BS1 threshold of >0.3%.	gnomad_v4
BS2	Not met	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.
BS3	Not met	No functional studies demonstrating normal splicing or protein function have been performed for this variant.
BS4	Not met	No family studies demonstrating lack of co-segregation with disease are available for this variant.
BP1	N/A	BP1 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.
BP2	Not met	No observation of this variant in cis with a known pathogenic MDM2 variant has been reported.
BP4	Not met	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.	spliceai bayesdel
BP5	Not met	No case has been identified in which this variant is found in an individual with an alternate molecular cause for disease.
BP6	Not met	No reputable source has classified this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 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.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.