12-68808800-T-G

Variant names:

• chr12-68808800-T-G
• rs2279744
• NM_002392.6:c.14+309T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002392.6(MDM2):​c.14+309T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 629,096 control chromosomes in the GnomAD database, including 37,754 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (9408 hom., cov: 32)
  • Exomes 𝑓: 0.34 (28346 hom.)
• Consequence: MDM2 NM_002392.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -1.76
• Publications: 446 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 12-68808800-T-G is Benign according to our data. Variant chr12-68808800-T-G is described in ClinVar as Benign. ClinVar VariationId is 13904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM2	NM_002392.6	MANE Select	c.14+309T>G		intron	N/A	NP_002383.2
	MDM2	NM_001145339.2		c.14+309T>G		intron	N/A	NP_001138811.1
	MDM2	NM_001367990.1		c.-291T>G		upstream_gene	N/A	NP_001354919.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM2	ENST00000258149.11	TSL:1 MANE Select	c.14+309T>G		intron	N/A	ENSP00000258149.6
	MDM2	ENST00000258148.11	TSL:1	c.14+309T>G		intron	N/A	ENSP00000258148.7
	MDM2	ENST00000393412.7	TSL:5	c.-5+309T>G		intron	N/A	ENSP00000377064.4

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48654 AN: 151752 Hom.: 9411 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.535

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.364

GnomAD4 exome AF: 0.336 AC: 160269 AN: 477226 Hom.: 28346 AF XY: 0.338 AC XY: 75832 AN XY: 224100

African (AFR) AF: 0.0730 AC: 665 AN: 9114

American (AMR) AF: 0.504 AC: 246 AN: 488

Ashkenazi Jewish (ASJ) AF: 0.506 AC: 1426 AN: 2818

East Asian (EAS) AF: 0.513 AC: 976 AN: 1902

South Asian (SAS) AF: 0.529 AC: 4805 AN: 9080

European-Finnish (FIN) AF: 0.411 AC: 60 AN: 146

Middle Eastern (MID) AF: 0.463 AC: 423 AN: 914

European-Non Finnish (NFE) AF: 0.334 AC: 146062 AN: 437400

Other (OTH) AF: 0.365 AC: 5606 AN: 15364

GnomAD4 genome AF: 0.320 AC: 48647 AN: 151870 Hom.: 9408 Cov.: 32 AF XY: 0.330 AC XY: 24522 AN XY: 74210

African (AFR) AF: 0.107 AC: 4419 AN: 41446

American (AMR) AF: 0.486 AC: 7408 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1774 AN: 3468

East Asian (EAS) AF: 0.534 AC: 2753 AN: 5152

South Asian (SAS) AF: 0.535 AC: 2577 AN: 4814

European-Finnish (FIN) AF: 0.424 AC: 4462 AN: 10520

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.355 AC: 24103 AN: 67894

Other (OTH) AF: 0.363 AC: 768 AN: 2116

Alfa AF: 0.287 Hom.: 3649

Bravo AF: 0.315

Asia WGS AF: 0.480 AC: 1670 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Accelerated tumor formation, susceptibility to Benign:1 Other:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 01, 2009

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.96
DANN	Benign	0.56
PhyloP100		-1.8
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.4
Mutation Taster		=100/0	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: rs2279744; hg19: chr12-69202580;