Submissions for variant NM_000546.6(TP53):c.423C>G (p.Cys141Trp)

dbSNP: rs1057519977

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000467641	SCV000545329	pathogenic	Li-Fraumeni syndrome	2023-07-28	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 29946497; Invitae). ClinVar contains an entry for this variant (Variation ID: 376564). 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, 20407015, 29979965, 30224644). This variant disrupts the p.Cys141 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10589545, 11370630, 12826609, 16861262, 21343334, 24256616). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 141 of the TP53 protein (p.Cys141Trp).
Ambry Genetics	RCV000492201	SCV000581134	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-11-15	criteria provided, single submitter	clinical testing	The p.C141W variant (also known as c.423C>G), located in coding exon 4 of the TP53 gene, results from a C to G substitution at nucleotide position 423. The cysteine at codon 141 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based assays and is predicted to affect several p53 isoforms (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003;8;100(14):8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Database of Curated Mutations (DoCM)	RCV000430241	SCV000507534	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440499	SCV000507535	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422816	SCV000507536	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434797	SCV000507537	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442353	SCV000507538	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423924	SCV000507539	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434169	SCV000507540	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444942	SCV000507541	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424802	SCV000507542	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431589	SCV000507543	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445034	SCV000507544	likely pathogenic	Papillary renal cell carcinoma type 1	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425931	SCV000507545	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only