ClinVar Miner

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

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Total submissions: 15
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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

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