ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.523C>T (p.Arg175Cys) (rs138729528)

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Total submissions: 27
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235329 SCV000293015 uncertain significance not provided 2015-10-10 criteria provided, single submitter clinical testing This variant is denoted TP53 c.523C>T at the cDNA level, p.Arg175Cys (R175C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant was identified through multigene testing in an individual with ovarian cancer whose personal and family history do not meet Chompret criteria for TP53 testing (Walsh 2011). Functional analyses have found that TP53 Arg175Cys retains normal transactivation or repression abilities for most p53 responsive elements, with a few studies demonstrating reduced transactivation of the BAX reporter (Ory 1994, Flaman 1998, Ryan 1998, Blagosklonny 2001). Activation of BAX by p53 initiates the apoptosis pathway, a key function of p53 in its role as a tumor suppressor. Ryan et al. (1998) demonstrated that TP53 Arg175Cys resulted in only a slight reduction in the percentage of cells undergoing apoptosis, which the authors summarized as essentially wild-type activity level. This variant is reported as having partially functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Arg175Cys was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Arg175Cys 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 Arg175Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000574439 SCV000664387 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
Invitae RCV000704159 SCV000833097 uncertain significance Li-Fraumeni syndrome 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 175 of the TP53 protein (p.Arg175Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs138729528, ExAC 0.006%). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 22006311, 28724667). ClinVar contains an entry for this variant (Variation ID: 245851). An experimental study in yeast has shown that this variant partially impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). Additional in-vitro analysis has demonstrated that this missense change results in retention of wild-type cell cycle arrest and apoptotic TP53 activities (PMID: 9632751). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Different missense substitutions at this codon (p.Arg175His, p.Arg175Gly) have been reported in many individuals and families affected with Li-Fraumeni syndrome, osteosarcoma, breast cancer and ovarian carcinoma (PMID: 11370630, 25927356, 8825920, 8164043, 21761402, 22006311). In addition, these variants have been reported to disrupt TP53 protein function and have been determined to be pathogenic (PMID: 23263379, 23792586, 21343334, 8062826, 9546439). 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.
Color RCV000574439 SCV000903055 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-08 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000439625 SCV000509158 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421969 SCV000509159 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433090 SCV000509160 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439855 SCV000509161 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423061 SCV000509162 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433333 SCV000509163 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444463 SCV000509164 likely pathogenic Nasopharyngeal Neoplasms 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426785 SCV000509165 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434308 SCV000509166 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442812 SCV000509167 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427794 SCV000509168 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438017 SCV000509169 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417778 SCV000509170 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424499 SCV000509171 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435664 SCV000509172 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418017 SCV000509173 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429015 SCV000509174 likely pathogenic Carcinoma of gallbladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439251 SCV000509175 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418929 SCV000509176 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429222 SCV000509177 likely pathogenic Chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440307 SCV000509178 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422641 SCV000509179 likely pathogenic Medulloblastoma 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785238 SCV000923806 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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