17-7676124-G-C

Position:

• chr17-7676124-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 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. P82L) has been classified as Pathogenic.

• 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

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7676124-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.30604345).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.245C>G	p.Pro82Arg	missense_variant	4/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.245C>G	p.Pro82Arg	missense_variant	4/11	1	NM_000546.6	ENSP00000269305.4

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2017

Experimental studies in yeast using site-directed mutagenesis have shown that TP53 proteins with this missense change retains functional transactivation activity (PMID: 12826609). 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. 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. 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. -

Computational scores

Source: dbNSFP v4.3

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;T;.;D;.;.;.;.;.;.;D;.;.;T;T;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.86	D;D;.;.;.;D;T;.;T;D;T;T;T;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.8	.;.;.;L;.;L;L;L;.;.;L;.;.;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.72	N;N;.;N;.;.;N;N;.;.;N;.;.;N;.;N
REVEL	Uncertain	0.55
Sift	Benign	0.064	T;T;.;T;.;.;T;T;.;.;T;.;.;D;.;D
Sift4G	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;.
Polyphen		0.36	B;.;.;P;.;P;B;P;.;.;P;.;.;D;.;.
Vest4		0.29
MutPred		0.29		Loss of glycosylation at P82 (P = 0.0118);Loss of glycosylation at P82 (P = 0.0118);.;Loss of glycosylation at P82 (P = 0.0118);.;Loss of glycosylation at P82 (P = 0.0118);Loss of glycosylation at P82 (P = 0.0118);Loss of glycosylation at P82 (P = 0.0118);.;.;Loss of glycosylation at P82 (P = 0.0118);.;Loss of glycosylation at P82 (P = 0.0118);Loss of glycosylation at P82 (P = 0.0118);Loss of glycosylation at P82 (P = 0.0118);Loss of glycosylation at P82 (P = 0.0118);
MVP		0.87
MPC		0.98
ClinPred		0.16	T
GERP RS		-0.43
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

Publications

LitVar

Other links and lift over

dbSNP: rs534447939; hg19: chr17-7579442;