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 |
RCV000424935 | SCV000507791 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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 |
RCV000442015 | SCV000507793 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425602 | SCV000507794 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436295 | SCV000507795 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419041 | SCV000507796 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426292 | SCV000507797 | likely pathogenic | Chronic lymphocytic leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436867 | SCV000507798 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419614 | SCV000507799 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430302 | SCV000507800 | likely pathogenic | Uterine Carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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, |
RCV000785282 | SCV000923850 | likely pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research |