rs1795480

Variant names:

• chr12-68828854-C-T
• rs1795480
• NM_002392.6:c.607C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-68828854-C-T
• chr12-68828854-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_002392.6(MDM2):​c.607C>T​(p.Leu203Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,613,910 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (35 hom., cov: 32)
  • Exomes 𝑓: 0.015 (190 hom.)
• Consequence: MDM2 NM_002392.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.63
• Publications: 13 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 12-68828854-C-T is Benign according to our data. Variant chr12-68828854-C-T is described in ClinVar as Benign. ClinVar VariationId is 472749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0182 (2766/152182) while in subpopulation AFR AF = 0.0282 (1169/41494). AF 95% confidence interval is 0.0268. There are 35 homozygotes in GnomAd4. There are 1321 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2766 AD,Unknown gene.

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.607C>T	p.Leu203Leu	synonymous	Exon 8 of 11	NP_002383.2	Q00987-11
	MDM2	NM_001367990.1		c.589C>T	p.Leu197Leu	synonymous	Exon 8 of 11	NP_001354919.1	Q00987-1
	MDM2	NM_001145337.3		c.589C>T	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.607C>T	p.Leu203Leu	synonymous	Exon 8 of 11	ENSP00000258149.6	Q00987-11
	MDM2	ENST00000539479.6	TSL:1	c.589C>T	p.Leu197Leu	synonymous	Exon 8 of 11	ENSP00000444430.2	Q00987-1
	MDM2	ENST00000350057.9	TSL:1	c.514C>T	p.Leu172Leu	synonymous	Exon 6 of 9	ENSP00000266624.9	J3KN53

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2760 AN: 152064 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0220

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0142 AC: 3546 AN: 249424 AF XY: 0.0141

Gnomad AFR exome AF: 0.0295

Gnomad AMR exome AF: 0.00620

Gnomad ASJ exome AF: 0.00576

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0225

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.0148 AC: 21685 AN: 1461728 Hom.: 190 Cov.: 31 AF XY: 0.0145 AC XY: 10565 AN XY: 727178

African (AFR) AF: 0.0298 AC: 997 AN: 33478

American (AMR) AF: 0.00704 AC: 315 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00501 AC: 131 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.00405 AC: 349 AN: 86256

European-Finnish (FIN) AF: 0.0217 AC: 1157 AN: 53404

Middle Eastern (MID) AF: 0.0116 AC: 67 AN: 5766

European-Non Finnish (NFE) AF: 0.0160 AC: 17782 AN: 1111906

Other (OTH) AF: 0.0147 AC: 886 AN: 60386

GnomAD4 genome AF: 0.0182 AC: 2766 AN: 152182 Hom.: 35 Cov.: 32 AF XY: 0.0178 AC XY: 1321 AN XY: 74410

African (AFR) AF: 0.0282 AC: 1169 AN: 41494

American (AMR) AF: 0.0109 AC: 166 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4822

European-Finnish (FIN) AF: 0.0220 AC: 233 AN: 10586

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0163 AC: 1111 AN: 68010

Other (OTH) AF: 0.0151 AC: 32 AN: 2114

Alfa AF: 0.0169 Hom.: 50

Bravo AF: 0.0185

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0171

EpiControl AF: 0.0162

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Accelerated tumor formation, susceptibility to (1)
-	-	1	MDM2-related condition (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	11
DANN	Benign	0.89
PhyloP100		1.6
Mutation Taster		=74/26	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: rs1795480; hg19: chr12-69222634; COSMIC: COSV50702801;