ClinVar Miner

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

dbSNP: rs1057519976
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 18
Download table as spreadsheet
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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.