12-68809237-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002392.6(MDM2):c.44C>T(p.Pro15Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000468 in 1,613,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: MDM2 NM_002392.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.901

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07069111).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDM2	NM_002392.6	c.44C>T	p.Pro15Leu	missense_variant	2/11	ENST00000258149.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDM2	ENST00000258149.11	c.44C>T	p.Pro15Leu	missense_variant	2/11	1	NM_002392.6

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152022 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000160 AC: 40 AN: 249550 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135388

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000344

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000498 AC: 728 AN: 1461768 Hom.: 0 Cov.: 31 AF XY: 0.000477 AC XY: 347 AN XY: 727202

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000610

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152022 Hom.: 0 Cov.: 33 AF XY: 0.0000943 AC XY: 7 AN XY: 74232

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000297 Hom.: 0

Bravo AF: 0.000166

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000611 AC: 5

ExAC AF: 0.000124 AC: 15

EpiCase AF: 0.000491

EpiControl AF: 0.000296

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

Invitae

Sep 03, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 15 of the MDM2 protein (p.Pro15Leu). This variant is present in population databases (rs201821879, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MDM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 856511). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	0.094
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.49
Cadd	Uncertain	24
Dann	Benign	0.97
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.046	N
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;.;.;.;D;D;D;.;D;D;.;.
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.071	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.54	D;D;D;D;D;D;D;D;D;D;D;D;D;N;N;N;N;N
PrimateAI	Benign	0.42	T
REVEL	Benign	0.061
Sift4G	Benign	0.24	T;T;D;T;T;T;D;D;T;T;D;D;D;D;D;D;T;D;D
Polyphen		0.0	B;.;B;B;B;.;.;.;.;.;B;B;B;B;.;B;.;.;.
Vest4		0.15
MVP		0.45
ClinPred		0.061	T
GERP RS		3.8
Varity_R		0.39
gMVP		0.20

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: rs201821879; hg19: chr12-69203017;