chr12-68828856-G-A

Variant names:

• chr12-68828856-G-A
• NM_002392.6:c.609G>A
• MDM2 p.Leu203Leu

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_002392.6(MDM2):​c.609G>A​(p.Leu203Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L203L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MDM2 NM_002392.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.348
• Publications: 0 publications found

Genes affected

MDM2 (HGNC:6973): (MDM2 proto-oncogene) This gene encodes a nuclear-localized E3 ubiquitin ligase. The encoded protein can promote tumor formation by targeting tumor suppressor proteins, such as p53, for proteasomal degradation. This gene is itself transcriptionally-regulated by p53. Overexpression or amplification of this locus is detected in a variety of different cancers. There is a pseudogene for this gene on chromosome 2. Alternative splicing results in a multitude of transcript variants, many of which may be expressed only in tumor cells. [provided by RefSeq, Jun 2013]

MDM2 Gene-Disease associations (from GenCC):

• Li-Fraumeni syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lessel-kubisch syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP7: Synonymous conserved (PhyloP=0.348 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002392.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM2	NM_002392.6	MANE Select	c.609G>A	p.Leu203Leu	synonymous	Exon 8 of 11	NP_002383.2	Q00987-11
	MDM2	NM_001367990.1		c.591G>A	p.Leu197Leu	synonymous	Exon 8 of 11	NP_001354919.1	Q00987-1
	MDM2	NM_001145337.3		c.591G>A	p.Leu197Leu	synonymous	Exon 8 of 11	NP_001138809.1	A0A0A8KB75

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM2	ENST00000258149.11	TSL:1 MANE Select	c.609G>A	p.Leu203Leu	synonymous	Exon 8 of 11	ENSP00000258149.6	Q00987-11
	MDM2	ENST00000539479.6	TSL:1	c.591G>A	p.Leu197Leu	synonymous	Exon 8 of 11	ENSP00000444430.2	Q00987-1
	MDM2	ENST00000350057.9	TSL:1	c.516G>A	p.Leu172Leu	synonymous	Exon 6 of 9	ENSP00000266624.9	J3KN53

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.5
DANN	Uncertain	0.98
PhyloP100		0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-69222636;

COSMIC: COSV50704128;

COSMIC: COSV50704128;