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 2019-08-13 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25584008, 17311302, 25743702, 24122735, 29489754, 20128691, 17606709, 26681312, 15722483, 12826609, 1631137, 29752319, 27323394, 1978757, 22803791, 23406775, 1565143, 21343334, 10629033, 16337994, 29979965, 16401470, 24573247, 30720243, 30840781)
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 2020-08-27 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 individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 1978757, 10922393, 23406775, 25584008, 26681312). ClinVar contains an entry for this variant (Variation ID: 12349). Experimental studies have shown that this variant affects TP53 protein function (PMID: 26205489, 1631137, 12826609, 20128691, 21343334). This variant disrupts the p.Gly245 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20128691, 21343334, 12917626, 15722483, 12826609, 1565143, 24122735, 17311302). 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.
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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