Submissions for variant NM_000546.6(TP53):c.541C>A (p.Arg181Ser)

dbSNP: rs587782596

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000799329	SCV001429623	uncertain significance	Li-Fraumeni syndrome	2020-08-11	reviewed by expert panel	curation	This variant has a BayesDel score >0.16 and Align GVGD (Zebrafish) is Class C65 (PP3_Moderate). This variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor). Transactivation assays show partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID: 12826609, 30224644). In summary, the clinical significance of TP53 c.541C>A (p.Arg181Ser) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Expert Panel: PP3_Moderate; BS3_Supporting; PM2_Supporting; BS2_Supporting.
Ambry Genetics	RCV000222957	SCV000274425	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-07	criteria provided, single submitter	clinical testing	The p.R181S variant (also known as c.541C>A), located in coding exon 4 of the TP53 gene, results from a C to A substitution at nucleotide position 541. The arginine at codon 181 is replaced by serine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have a partial loss of transactivation capacity and predicted to affect several p53 isoforms. (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Other variants at this same codon (p.R181H, p.R181P and p.R181C) have been reported to be associated with early onset breast and brain cancers (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). However, studies conducted in human cell lines for p.R181S indicate this alteration remains proficient at growth suppression (Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). This amino acid position is well conserved through mammals. 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.
Color Diagnostics, LLC DBA Color Health	RCV000222957	SCV000686748	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with serine at codon 181 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant does not impair TP53 protein function. The mutant protein was partially functional in yeast transactivation assays (IARC database and PMID: 12826609), did not show dominant negative or loss of function in human cell growth suppression assays (PMID: 30224644) and was functional in human cell proliferation assay (PMID: 29979965). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same position, p.Arg181His and p.Arg181Cys, are known to be pathogenic (Clinvar variation ID: 142320 and 142624), indicating the importance of arginine at this position for TP53 function. However, the available clinical and functional evidence is insufficient to determine the role of this particular variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000799329	SCV000938988	uncertain significance	Li-Fraumeni syndrome	2022-09-13	criteria provided, single submitter	clinical testing	Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 230764). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 181 of the TP53 protein (p.Arg181Ser). Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). 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.