ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.405C>G (p.Cys135Trp) (rs1057519976)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Database of Curated Mutations (DoCM) RCV000434979 SCV000507483 likely pathogenic Neoplasm of the breast 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 Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441628 SCV000507489 likely pathogenic Adenocarcinoma of stomach 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 Adrenocortical 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
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 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 135 of the TP53 protein (p.Cys135Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 376561). Experimental evidence using yeast-based functional assays have shown that this missense change results in partial loss of TP53 transactivation activity (PMID: 12826609). 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.

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