17-7676537-A-G

Variant names:

• chr17-7676537-A-G
• rs876659913
• NM_000546.6:c.58T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000546.6(TP53):​c.58T>C​(p.Ser20Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.08

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a mutagenesis_site Constitutively increased TP53 protein levels. (size 0) in uniprot entity P53_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.58T>C	p.Ser20Pro	missense_variant	Exon 2 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.58T>C	p.Ser20Pro	missense_variant	Exon 2 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461784 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1

Mar 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 20 of the TP53 protein (p.Ser20Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 232673). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 24594805). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Sep 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S20P variant (also known as c.58T>C), located in coding exon 1 of the TP53 gene, results from a T to C substitution at nucleotide position 58. The serine at codon 20 is replaced by proline, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no dominant negative effect (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). The serine at position 20 has been shown to be a target of phosphorylation in response to DNA damage leading to stabilization of the p53 protein; however, the clinical consequences of the alteration of this phosphorylation site can not be determined (Chehab NH, Proc. Natl. Acad. Sci. U.S.A. 1999 Nov; 96(24):13777-82. Chehab NH, Genes Dev. 2000 Feb; 14(3):278-88). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T;T;D;.;.;.;D;.;T;T;T;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.78	T;T;.;T;T;.;T;T;D;T;T;T
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	2.0	.;.;M;M;M;M;M;.;.;.;.;.
PROVEAN	Benign	-1.1	N;N;N;.;N;N;N;.;N;N;.;N
REVEL	Pathogenic	0.75
Sift	Benign	0.10	T;T;T;.;T;T;T;.;D;T;.;D
Sift4G	Benign	0.23	T;T;T;T;T;T;T;T;.;.;T;.
Polyphen		0.99	D;.;B;B;D;B;B;.;B;D;.;.
Vest4		0.51
MutPred		0.51		Loss of phosphorylation at S20 (P = 0.0657);Loss of phosphorylation at S20 (P = 0.0657);Loss of phosphorylation at S20 (P = 0.0657);Loss of phosphorylation at S20 (P = 0.0657);Loss of phosphorylation at S20 (P = 0.0657);Loss of phosphorylation at S20 (P = 0.0657);Loss of phosphorylation at S20 (P = 0.0657);Loss of phosphorylation at S20 (P = 0.0657);Loss of phosphorylation at S20 (P = 0.0657);Loss of phosphorylation at S20 (P = 0.0657);Loss of phosphorylation at S20 (P = 0.0657);Loss of phosphorylation at S20 (P = 0.0657);
MVP		0.96
MPC		0.91
ClinPred		0.55	D
GERP RS		3.1
Varity_R		0.66
gMVP		0.50

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: rs876659913; hg19: chr17-7579855;