Submissions for variant NM_000546.5(TP53):c.824G>A (p.Cys275Tyr) (rs863224451)

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000197359	SCV000253702	pathogenic	Li-Fraumeni syndrome	2019-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with tyrosine at codon 275 of the TP53 protein (p.Cys275Tyr). 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 (ExAC no frequency). This variant has been observed in several individuals and families affected with Li-Fraumeni syndrome (PMID: 7887414, 14584079, 17606709, Invitae), and an individual affected with chronic lymphocytic leukemia (PMID: 19850740). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 215997). Functional analysis of this variant in transactivation assays using yeast model system shows this variant is non-functional (PMID: 12826609, 21343334). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000235315	SCV000293284	pathogenic	not provided	2015-10-26	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted TP53 c.824G>A at the cDNA level, p.Cys275Tyr (C275Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant has been reported in at least two families with multiple sarcomas meeting Chompret criteria (Frebourg 1995, Lynch 2003). Multiple yeast- and tumor-based functional assays have found that TP53 Cys275Tyr eliminates or greatly reduces transcriptional activity of several p53-responsive elements (Tada 1997, Flaman 1998, Marutani 1999, Waddell 2001, Deissler 2004). This variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003) and is classified as a severe deficiency allele by Monti et al. (2011). TP53 Cys275Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Cys275Tyr occurs at a position that is conserved across species and is located in the DNA binding domain and region of interaction with multiple proteins (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics	RCV000568594	SCV000664383	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-11	criteria provided, single submitter	clinical testing	The p.C275Y pathogenic mutation (also known as c.824G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 824. The cysteine at codon 275 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation was identified as a germline alteration in three individuals from a family with Li-Fraumeni syndrome (LFS), where the proband had a rhabadomyosarcoma at 2 years of age, the father with sarcoma at 34y, and a paternal uncle with sarcoma at 22y and 27y (Frebourg T et al. Am. J. Hum. Genet. 1995 Mar; 56(3):608-15). This mutation has also been identified as a germline alteration in a separate LFS family, where 16 family members had 18 sarcomas of various types, as well as breast cancer and leukemia (Lynch HT et al. Cancer. 2003 Nov 1;98(9):1947-57). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and dominant negative effect in yeast-based assays (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P, Mol. Cancer Res. 2011 Mar; 9(3):271-9). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and is deficient at growth suppression in vitro (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 has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). In addition, residue 275 of the p53 protein has been shown by crystal structure to be involved in DNA contact (Martin AC et al. Hum. Mutat. 2002 Feb; 19(2):149-64). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color	RCV000568594	SCV001359331	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-04-10	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000439245	SCV000507824	likely pathogenic	Ovarian Serous Cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422025	SCV000507825	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429197	SCV000507826	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439892	SCV000507827	likely pathogenic	Chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422663	SCV000507828	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433358	SCV000507829	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443293	SCV000507830	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423497	SCV000507831	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434190	SCV000507832	likely pathogenic	Renal cell carcinoma, papillary, 1	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442329	SCV000507833	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427629	SCV000507834	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438333	SCV000507835	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442357	SCV000507836	likely pathogenic	Adrenocortical carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424784	SCV000507837	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435410	SCV000507838	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418175	SCV000507839	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne	RCV000785533	SCV000924105	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research