Submissions for variant NM_000546.6(TP53):c.823T>C (p.Cys275Arg)

dbSNP: rs1057519983

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001183954	SCV001349812	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with arginine at codon 275 in the DNA binding domain of the TP53 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Different variants affecting the same position, p.Cys275Trp and p.Cys275Tyr, are considered to be disease-causing (ClinVar variation ID: 485044, 215997), suggesting that cysteine or similar amino acid at this position is important for the protein function. Multiple functional studies have shown that the mutant protein is non-functional in growth suppression, cell proliferation and transactivation assays (PMID: 12826609, 21343334, 30224644 and IARC database) and has a dominant-negative effect on growth suppression (PMID: 30224644). This variant has been observed in individuals affected with early-onset breast cancer (PMID: 31119730), acute myeloid leukemia (PMID: 32164171) and Li-Fraumeni-like syndrome (PMID: 35033608). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon, p.Cys275Trp and p.Cys275Tyr, are thought to be disease-causing and have been observed in individuals affected with Li-Fraumeni syndrome (ClinVar variation ID: 485044, 215997), indicating that cysteine at this position is important for TP53 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae	RCV002521507	SCV003443710	uncertain significance	Li-Fraumeni syndrome	2022-08-27	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 function (PMID: 12826609, 29979965, 30224644). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 376584). This missense change has been observed in individual(s) with TP53-related conditions (PMID: 28724667, 31119730). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 275 of the TP53 protein (p.Cys275Arg).
Database of Curated Mutations (DoCM)	RCV000433579	SCV000507872	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443110	SCV000507873	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426139	SCV000507874	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432909	SCV000507875	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442259	SCV000507876	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425483	SCV000507877	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435695	SCV000507878	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418020	SCV000507879	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424757	SCV000507880	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435015	SCV000507881	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420853	SCV000507882	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431136	SCV000507883	likely pathogenic	Papillary renal cell carcinoma type 1	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441393	SCV000507884	likely pathogenic	B-cell chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420225	SCV000507885	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430390	SCV000507886	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440640	SCV000507887	likely pathogenic	Adrenal cortex carcinoma	2016-05-31	no assertion criteria provided	literature only