Submissions for variant NM_000546.6(TP53):c.405C>G (p.Cys135Trp)

dbSNP: rs1057519976

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479510	SCV000567571	uncertain significance	not provided	2015-08-10	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.405C>G at the cDNA level, p.Cys135Trp (C135W) at the protein level, and results in the change of a Cysteine to a Tryptophan (TGC>TGG). This variant has not, to our knowledge, been published in the literature as a germline variant; however, TP53 Cys135Trp has been reported as a somatic variant in multiple different tumor types (IARC TP53 Database). This variant is reported as having partially functional transactivation activity, an important function of the p53 protein, in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). However, similar assays by other researchers found significantly decreased transactivation activity (Tada 1997, Chappuis 1999). TP53 Cys135Trp was not found to cause a dominant-negative effect in additional transactivation studies by Marutani et al. (1999).TP53 Cys135Trp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Cysteine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Cys135Trp occurs at a position that is conserved across species and is located in the DNA binding domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether TP53 Cys135Trp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000556410	SCV000629820	uncertain significance	Li-Fraumeni syndrome	2023-07-15	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 135 of the TP53 protein (p.Cys135Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 376561). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). 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.
Genome-Nilou Lab	RCV002289519	SCV002582089	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289518	SCV002582652	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002289519	SCV002631332	likely pathogenic	Hereditary cancer-predisposing syndrome	2015-12-07	criteria provided, single submitter	clinical testing	The p.C135W variant (also known as c.405C>G), located in coding exon 4 of the TP53 gene, results from a C to G substitution at nucleotide position 405. The cysteine at codon 135 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant has been reported as a somatic mutation multiple times in various tumors, but not as a germline mutation by the IARC TP53 database. It is located in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based assays (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Shiraishi Ket al. J. Biol. Chem. 2004 Jan; 279(1):348-55. Chappuis P et al. Int. J. Cancer 1999 Dec; 84(6):587-93). In addition, structural analysis suggests this variant, which is a buried residue in the secondary shell of the DNA binding surface, is structurally destabilizing (Cho Y et al. Science. 1994 Jul 15;265(5170):346-55). 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 current evidence, p.C135W is interpreted as a likely pathogenic moderate risk allele that may not be associated with classic LFS. Clinical correlation is advised.
Database of Curated Mutations (DoCM)	RCV000434979	SCV000507483	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417767	SCV000507484	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424924	SCV000507485	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435704	SCV000507486	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420220	SCV000507487	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430892	SCV000507488	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441628	SCV000507489	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420893	SCV000507490	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429841	SCV000507491	likely pathogenic	Adrenal cortex carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440498	SCV000507492	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423274	SCV000507493	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432245	SCV000507494	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439451	SCV000507495	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only