rs1555524361

Positions:

• chr17-7670628-C-G
• chr17-7670628-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The ENST00000269305.9(TP53):​c.1081G>C​(p.Gly361Arg) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G361E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 ENST00000269305.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 1.12

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 2 ACMG points.

• PM1: In a region_of_interest Interaction with HIPK1 (size 270) in uniprot entity P53_HUMAN there are 520 pathogenic changes around while only 147 benign (78%) in ENST00000269305.9
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2175084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.1081G>C	p.Gly361Arg	missense_variant	10/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.1081G>C	p.Gly361Arg	missense_variant	10/11	1	NM_000546.6	ENSP00000269305	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 27, 2023	The p.G361R variant (also known as c.1081G>C), located in coding exon 9 of the TP53 gene, results from a G to C substitution at nucleotide position 1081. The glycine at codon 361 is replaced by arginine, an amino acid with dissimilar properties. This variant is reported to have partially 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).This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

Li-Fraumeni syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 18, 2022

- -

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 361 of the TP53 protein (p.Gly361Arg). 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: 480761). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TP53 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609). 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. -

Adrenocortical carcinoma, hereditary Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	17
DANN	Benign	0.76
DEOGEN2	Uncertain	0.56	.;.;.;D;.;D;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.91	D;D;.;.;.;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	1.5	.;.;.;L;.;L;.;.
MutationTaster	Benign	0.74	D;D;D;D;D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.1	.;.;.;N;.;N;.;.
REVEL	Uncertain	0.36
Sift	Benign	0.45	.;.;.;T;.;T;.;.
Sift4G	Benign	0.51	T;T;T;T;T;T;T;T
Polyphen		0.0070	.;.;.;B;.;B;.;.
Vest4		0.29
MutPred		0.18		.;.;.;Gain of solvent accessibility (P = 0.0097);.;Gain of solvent accessibility (P = 0.0097);.;.;
MVP		0.72
MPC		0.29
ClinPred		0.31	T
GERP RS		5.4
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.3
Varity_R		0.17
gMVP		0.21

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: rs1555524361; hg19: chr17-7573946;