chr17-7676124-G-C

Variant names:

• chr17-7676124-G-C
• rs534447939
• NM_000546.6:c.245C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000546.6(TP53):​c.245C>G​(p.Pro82Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P82A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.780
• Publications: 42 publications found

Genes affected

TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

TP53 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• Li-Fraumeni syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• Li-Fraumeni syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• adrenocortical carcinoma, hereditary

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• bone marrow failure syndrome 5

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• colorectal cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• choroid plexus carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30604345).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000546.6. 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
	TP53	NM_000546.6	MANE Select	c.245C>G	p.Pro82Arg	missense	Exon 4 of 11	NP_000537.3
	TP53	NM_001126112.3		c.245C>G	p.Pro82Arg	missense	Exon 4 of 11	NP_001119584.1
	TP53	NM_001407262.1		c.245C>G	p.Pro82Arg	missense	Exon 5 of 12	NP_001394191.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.245C>G	p.Pro82Arg	missense	Exon 4 of 11	ENSP00000269305.4
	TP53	ENST00000445888.6	TSL:1	c.245C>G	p.Pro82Arg	missense	Exon 4 of 11	ENSP00000391478.2
	TP53	ENST00000610292.4	TSL:1	c.128C>G	p.Pro43Arg	missense	Exon 3 of 10	ENSP00000478219.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1

Jan 18, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change that does not appear to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TP53-related disease. This sequence change replaces proline with arginine at codon 82 of the TP53 protein (p.Pro82Arg). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and arginine. Experimental studies in yeast using site-directed mutagenesis have shown that TP53 proteins with this missense change retains functional transactivation activity (PMID: 12826609).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	11
DANN	Benign	0.94
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.8	L
PhyloP100		0.78
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.72	N
REVEL	Uncertain	0.55
Sift	Benign	0.064	T
Sift4G	Benign	0.24	T
Polyphen		0.36	B
Vest4		0.29
MutPred		0.29		Loss of glycosylation at P82 (P = 0.0118)
MVP		0.87
MPC		0.98
ClinPred		0.16	T
GERP RS		-0.43
PromoterAI		-0.028	Neutral
Varity_R		0.10
gMVP		0.35

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: rs534447939; hg19: chr17-7579442;