12-68809273-C-T

Variant names:

• chr12-68809273-C-T
• NM_002392.6:c.80C>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.80C>T​(p.Ala27Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,808 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: 0.0000027 (0 hom.)
• Consequence: MDM2 NM_002392.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.07

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=0.25445944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM2	NM_002392.6	c.80C>T	p.Ala27Val	missense_variant	Exon 2 of 11	ENST00000258149.11	NP_002383.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM2	ENST00000258149.11	c.80C>T	p.Ala27Val	missense_variant	Exon 2 of 11	1	NM_002392.6	ENSP00000258149.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461808 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000331

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

Apr 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 27 of the MDM2 protein (p.Ala27Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MDM2-related conditions. 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 disruptive. 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	0.13
BayesDel_addAF	Benign	-0.0033	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	.;T;T;T;D;T;.;.;.;.;T;.;.;.;.;.;T;T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.45	N
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;.;.;.;D;D;D;.;D;D;.;.
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.2	.;.;.;.;M;.;.;.;.;.;.;M;M;.;.;M;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.5	.;N;N;N;N;N;D;D;N;N;N;N;N;N;D;N;N;N;D
REVEL	Benign	0.12
Sift	Benign	0.17	.;T;D;D;D;D;D;D;.;D;D;D;T;T;D;D;D;T;.
Sift4G	Uncertain	0.015	D;D;D;D;D;D;T;T;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.98	D;.;B;B;D;.;.;.;.;.;B;B;B;P;.;B;.;.;.
Vest4		0.39
MutPred		0.19		.;Gain of catalytic residue at Q18 (P = 0.101);Gain of catalytic residue at Q18 (P = 0.101);.;Gain of catalytic residue at Q18 (P = 0.101);Gain of catalytic residue at Q18 (P = 0.101);Gain of catalytic residue at Q18 (P = 0.101);Gain of catalytic residue at Q18 (P = 0.101);Gain of catalytic residue at Q18 (P = 0.101);Gain of catalytic residue at Q18 (P = 0.101);Gain of catalytic residue at Q18 (P = 0.101);Gain of catalytic residue at Q18 (P = 0.101);Gain of catalytic residue at Q18 (P = 0.101);Gain of catalytic residue at Q18 (P = 0.101);Gain of catalytic residue at Q18 (P = 0.101);Gain of catalytic residue at Q18 (P = 0.101);Gain of catalytic residue at Q18 (P = 0.101);.;.;
MVP		0.60
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.61
gMVP		0.48

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-69203053;