rs769412

Variant names:

• chr12-68839435-A-G
• rs769412
• NM_002392.6:c.1080A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002392.6(MDM2):​c.1080A>G​(p.Glu360Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0622 in 1,613,782 control chromosomes in the GnomAD database, including 3,502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (510 hom., cov: 31)
  • Exomes 𝑓: 0.061 (2992 hom.)
• Consequence: MDM2 NM_002392.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.282
• Publications: 47 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 12-68839435-A-G is Benign according to our data. Variant chr12-68839435-A-G is described in ClinVar as Benign. ClinVar VariationId is 1167676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.282 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM2	NM_002392.6	c.1080A>G	p.Glu360Glu	synonymous_variant	Exon 11 of 11	ENST00000258149.11	NP_002383.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM2	ENST00000258149.11	c.1080A>G	p.Glu360Glu	synonymous_variant	Exon 11 of 11	1	NM_002392.6	ENSP00000258149.6

Frequencies

GnomAD3 genomes AF: 0.0739 AC: 11222 AN: 151810 Hom.: 513 Cov.: 31

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0676

Gnomad ASJ AF: 0.0375

Gnomad EAS AF: 0.0143

Gnomad SAS AF: 0.0551

Gnomad FIN AF: 0.0233

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0599

Gnomad OTH AF: 0.0755

GnomAD2 exomes AF: 0.0548 AC: 13680 AN: 249520 AF XY: 0.0544

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.0407

Gnomad ASJ exome AF: 0.0410

Gnomad EAS exome AF: 0.0161

Gnomad FIN exome AF: 0.0287

Gnomad NFE exome AF: 0.0608

Gnomad OTH exome AF: 0.0589

GnomAD4 exome AF: 0.0610 AC: 89135 AN: 1461854 Hom.: 2992 Cov.: 31 AF XY: 0.0607 AC XY: 44176 AN XY: 727226

African (AFR) AF: 0.128 AC: 4296 AN: 33480

American (AMR) AF: 0.0433 AC: 1937 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0421 AC: 1101 AN: 26132

East Asian (EAS) AF: 0.0170 AC: 675 AN: 39688

South Asian (SAS) AF: 0.0589 AC: 5079 AN: 86256

European-Finnish (FIN) AF: 0.0312 AC: 1668 AN: 53416

Middle Eastern (MID) AF: 0.0673 AC: 388 AN: 5768

European-Non Finnish (NFE) AF: 0.0631 AC: 70202 AN: 1111996

Other (OTH) AF: 0.0627 AC: 3789 AN: 60394

GnomAD4 genome AF: 0.0739 AC: 11230 AN: 151928 Hom.: 510 Cov.: 31 AF XY: 0.0719 AC XY: 5336 AN XY: 74220

African (AFR) AF: 0.126 AC: 5211 AN: 41426

American (AMR) AF: 0.0674 AC: 1026 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.0375 AC: 130 AN: 3470

East Asian (EAS) AF: 0.0142 AC: 73 AN: 5146

South Asian (SAS) AF: 0.0551 AC: 266 AN: 4824

European-Finnish (FIN) AF: 0.0233 AC: 246 AN: 10552

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0599 AC: 4069 AN: 67974

Other (OTH) AF: 0.0752 AC: 159 AN: 2114

Alfa AF: 0.0659 Hom.: 323

Bravo AF: 0.0797

Asia WGS AF: 0.0420 AC: 146 AN: 3478

EpiCase AF: 0.0637

EpiControl AF: 0.0666

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Accelerated tumor formation, susceptibility to Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.9
DANN	Benign	0.71
PhyloP100		0.28
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs769412; hg19: chr12-69233215; COSMIC: COSV50699998; COSMIC: COSV50699998;