12-68809278-G-A

Position:

• chr12-68809278-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002392.6(MDM2):​c.85G>A​(p.Glu29Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MDM2 NM_002392.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29592228).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MDM2	NM_002392.6	c.85G>A	p.Glu29Lys	missense_variant	2/11	ENST00000258149.11	NP_002383.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MDM2	ENST00000258149.11	c.85G>A	p.Glu29Lys	missense_variant	2/11	1	NM_002392.6	ENSP00000258149.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249552 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135390

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461792 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Accelerated tumor formation, susceptibility to Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals affected with MDM2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 29 of the MDM2 protein (p.Glu29Lys). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	.;T;T;T;D;T;.;.;.;.;T;.;.;.;.;.;T;T;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;.;.;.;D;D;D;.;D;D;.;.
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.3	.;.;.;.;M;.;.;.;.;.;.;M;M;.;.;M;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.1	.;N;N;N;N;N;D;D;N;D;N;N;N;N;D;N;N;N;D
REVEL	Benign	0.11
Sift	Benign	0.10	.;T;D;T;T;T;D;D;.;T;D;D;D;T;D;D;D;T;.
Sift4G	Benign	0.18	T;T;D;T;T;D;T;T;T;D;D;D;T;T;D;D;D;T;D
Polyphen		0.92	P;.;D;P;P;.;.;.;.;.;D;D;D;D;.;D;.;.;.
Vest4		0.36
MutPred		0.28		.;Gain of ubiquitination at E23 (P = 0.0051);Gain of ubiquitination at E23 (P = 0.0051);.;Gain of ubiquitination at E23 (P = 0.0051);Gain of ubiquitination at E23 (P = 0.0051);Gain of ubiquitination at E23 (P = 0.0051);Gain of ubiquitination at E23 (P = 0.0051);Gain of ubiquitination at E23 (P = 0.0051);Gain of ubiquitination at E23 (P = 0.0051);Gain of ubiquitination at E23 (P = 0.0051);Gain of ubiquitination at E23 (P = 0.0051);Gain of ubiquitination at E23 (P = 0.0051);Gain of ubiquitination at E23 (P = 0.0051);Gain of ubiquitination at E23 (P = 0.0051);Gain of ubiquitination at E23 (P = 0.0051);Gain of ubiquitination at E23 (P = 0.0051);.;.;
MVP		0.63
ClinPred		0.91	D
GERP RS		5.0
Varity_R		0.68
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs1361311287; hg19: chr12-69203058; COSMIC: COSV50699691; COSMIC: COSV50699691;