Submissions for variant NM_000546.5(TP53):c.725G>A (p.Cys242Tyr) (rs121912655)

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129809	SCV000184623	pathogenic	Hereditary cancer-predisposing syndrome	2019-02-06	criteria provided, single submitter	clinical testing	The p.C242Y (also known as c.725G>A) pathogenic mutation is located in coding exon 6 of the TP53 gene. This variant results from a G to A substitution at nucleotide position 725, and the cysteine at codon 242 is replaced by tyrosine, an amino acid with highly dissimilar properties. This pathogenic mutation 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(5170):346-55). This variant is also reported to have loss of transactivation capacity, dominant negative effect and predicted to affect several p53 isoforms in yeast based assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9; Rainwater R et al. Mol. Cell. Biol. 1995 Jul;15(7):3892-903). This p.C242Y mutation has been detected in multiple individuals/families satisfying criteria for Li-Fraumeni syndrome (Blanco A et al. Clin Genet. 2010 Feb;77(2):193-6; Metzger AK et al. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7825-9; McIntyre JF et al. J Clin Oncol. 1994 May;12(5):925-30; Ambry internal data). In addition, another missense alteration at codon 242, p.C242R, has been reported as pathogenic in a woman with the following clinical history: 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 (Heymann S et al. Radiat Oncol. 2010 Nov 8;5:104). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000231770	SCV000285209	pathogenic	Li-Fraumeni syndrome	2019-08-26	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with tyrosine at codon 242 of the TP53 protein (p.Cys242Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (rs121912655, ExAC no frequency). This variant has been reported in individuals with Li-Fraumeni syndrome associated tumors (PMID: 1679237, 8164043, 9839505, 25896519, Invitae) and breast cancer (PMID: 19930417, 27276934). ClinVar contains an entry for this variant (Variation ID: 12354). This variant is in the DNA binding domain (PMID: 8023157) in one of the four regions where TP53 mutations are clustered (PMID: 2531845, 2554494). Experimental studies have shown that this missense change is non-functional or dominant negative allele based on transactivation activity (PMID: 9364015, 12826609, 12726864, 12917626, 11429705, 21343334, 20407015). A different missense substitution at this codon (p.Cys242Arg) has been reported in individuals with osteosarcoma and breast cancer (PMID: 21059199, 25896519, 18511570, 20805372). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000013148	SCV000033395	pathogenic	Li-Fraumeni-like syndrome	1995-01-01	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424935	SCV000507791	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432119	SCV000507792	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442015	SCV000507793	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425602	SCV000507794	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436295	SCV000507795	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419041	SCV000507796	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426292	SCV000507797	likely pathogenic	Chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436867	SCV000507798	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419614	SCV000507799	likely pathogenic	Adenocarcinoma of stomach	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430302	SCV000507800	likely pathogenic	Uterine Carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440992	SCV000507801	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne	RCV000785282	SCV000923850	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research