ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.733G>T (p.Gly245Cys) (rs28934575)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000161025 SCV000211746 pathogenic not provided 2019-01-15 criteria provided, single submitter clinical testing This variant is denoted TP53 c.733G>T at the cDNA level, p.Gly245Cys (G245C) at the protein level, and results in the change of a Glycine to a Cysteine (GGC>TGC) in exon 7. This variant was observed in a child with osteosarcoma whose family met classic Li-Fraumeni syndrome criteria and another child with adrenocortical carcinoma (Malkin 1990, Pinto 2013). Multiple functional studies have found this variant to significantly impact growth suppression, apoptosis, DNA binding, and transactivation activities and to result in a dominant-negative effect (Frebourg 1992, Aurelio 2000, Malcikova 2010, Monti 2011). Consistent with these data, this variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Gly245Cys was not observed in large population cohorts (Lek 2016). This variant is located at a residue that binds the Zinc ion within the DNA binding domain (Bode 2004, Pintus 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the current evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000492412 SCV000581089 pathogenic Hereditary cancer-predisposing syndrome 2015-04-02 criteria provided, single submitter clinical testing The p.G245C pathogenic mutation (also known as c.733G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at nucleotide position 733. The glycine at codon 245 is replaced by cysteine, an amino acid with highly dissimilar properties.This mutation was first described in a patient diagnosed with anosteosarcomaat age 11, and two first degree relatives that developed sarcomas at ages 19 and 58(Malkinet al. Science. 1990 Nov 30;250(4985):1233-8.) Several yeast-based functional studieshave categorized the p.G245C mutation as a severe deficiency, or non-functional allele because it is devoid of transactivation capacity (MontiP, Mol. Cancer Res. 2011 Mar; 9(3):271-9;Kato S et al.Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). One of these studies demonstrated that the G245 allele has amoderate dominant negative effectwhen combined with the wild type p53 allele(MontiP, Mol. Cancer Res. 2011 Mar; 9(3):271-9). Another group showed the p.G245C mutation leading to greatly reduced DNA binding ability compared to wild-type p53 (Malcikovaet al.BiolChem. 2010Feb-Mar;391(2-3):197-205). In addition, this location is a mutation hotspot, with multiple other alterations at this same codon being described in individuals with Li-Fraumeni Syndrome (SrivastavaS, Nature 1990 Dec.; 348(6303):747-9. Wong P,Gastroenterology2006 Jan; 130(1):73-9. Xu J, Sci Rep 2014 ; 4():4223). Based on the supporting evidence, p.G245C is interpreted as a disease-causing mutation.<br /> 
Invitae RCV000633397 SCV000754619 pathogenic Li-Fraumeni syndrome 2019-08-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 245 of the TP53 protein (p.Gly245Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in families affected with Li-Fraumeni syndrome (LFS) or LFS-like syndrome (PMID: 1978757, 10922393, 23406775), an individual affected with adrenocortical carcinoma (PMID: 25584008) and in an individual affected with ovarian cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 12349). This variant is located within the DNA binding domain, which is important for proper TP53 protein function (PMID: 26205489). Experimental studies have shown that this missense change disrupts the ability of TP53 protein to bind to DNA and significantly decreases its transcriptional transactivation activity and tumor suppressor function (PMID: 1631137 12826609, 20128691, 21343334). A different missense substitution at this codon (p.Gly245Ser) has been determined to be pathogenic (PMID: 20128691, 21343334, 12917626, 15722483, 12826609, 1565143, 24122735, 17311302). This suggests that the glycine residue is critical for TP53 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000013142 SCV000033389 pathogenic Li-Fraumeni syndrome 1 1992-07-15 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443435 SCV000508231 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425471 SCV000508232 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436186 SCV000508233 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417593 SCV000508234 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426090 SCV000508235 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436330 SCV000508236 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418673 SCV000508237 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428895 SCV000508238 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440886 SCV000508239 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419737 SCV000508240 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430002 SCV000508241 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440197 SCV000508242 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424262 SCV000508243 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434535 SCV000508244 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441334 SCV000508245 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423577 SCV000508246 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
CZECANCA consortium RCV001271056 SCV001451875 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing

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