Submissions for variant NM_000546.6(TP53):c.724T>C (p.Cys242Arg)

dbSNP: rs1057519982

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523905	SCV000617734	pathogenic	not provided	2022-04-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation and impaired growth suppression ability (Kato 2003, Kotler 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30840781, 19367287, 20581117, 20805372, 12209590, 24550057, 17947339, 23772609, 18511570, 25896519, 29979965, 15541116, 34099734, 15510160, Sasa_2022, 21059199)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000523905	SCV002011364	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857954	SCV002140195	uncertain significance	Li-Fraumeni syndrome	2021-07-30	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects TP53 protein function (PMID: 12826609, 29979965, 30224644). 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 expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 449512). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 18511570, 20805372, 21059199, 25896519). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 242 of the TP53 protein (p.Cys242Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine.
Ambry Genetics	RCV002376961	SCV002671456	pathogenic	Hereditary cancer-predisposing syndrome	2020-02-20	criteria provided, single submitter	clinical testing	The p.C242R pathogenic mutation (also known as c.724T>C), located in coding exon 6 of the TP53 gene, results from a T to C substitution at nucleotide position 724. The cysteine at codon 242 is replaced by arginine, an amino acid with highly dissimilar properties. This pathogenic mutation has been reported in multiple early onset breast cancer patients including one woman who was diagnosed with phyllodes breast tumor at age 22, liposarcoma at age 26, contralateral breat cancer at age 29 and ipsilateral recurrence within the radiation field at age 33, and chest wall angiosarcoma at age 35 (Wilson JR et al. J. Med. Genet. 2010 Nov;47:771-4; Heymann S et al. Radiat Oncol. 2010 Nov;5:104). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient 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 alteration is located in the functionally critical DNA binding domain, and it is one of four amino acid residues required for zinc binding and protein stabilization (Cho Y et al. Science. 1994 Jul;265:346-55). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV004023543	SCV004930933	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-16	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].