Submissions for variant NM_000546.6(TP53):c.733G>T (p.Gly245Cys)

dbSNP: rs28934575

Total submissions: 24

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	2022-05-13	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 an osteosarcoma at age 11, and two first degree relatives that developed sarcomas at ages 19 and 58 (Malkin et al. Science. 1990 Nov 30;250(4985):1233-8.) This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Another group showed the p.G245C mutation leading to greatly reduced DNA binding ability compared to wild-type p53 (Malcikova et al. Biol Chem. 2010 Feb-Mar;391(2-3):197-205). In addition, this site is a mutation hotspot, with multiple other alterations at this same codon being described in individuals with Li-Fraumeni Syndrome (Srivastava S et al. Nature. 1990 Dec.; 348(6303):747-9; Wong P et al. Gastroenterology. 2006 Jan; 130(1):73-9; Xu J et al. Sci Rep. 2014 ; 4():4223). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000633397	SCV000754619	pathogenic	Li-Fraumeni syndrome	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 245 of the TP53 protein (p.Gly245Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 1978757, 10922393, 23406775, 25584008, 26681312). ClinVar contains an entry for this variant (Variation ID: 12349). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 1631137, 12826609, 20128691, 21343334, 26205489). 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: 1565143, 12826609, 12917626, 15722483, 17311302, 20128691, 21343334, 24122735). 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.
Genome-Nilou Lab	RCV000492412	SCV002582466	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000013142	SCV002583127	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000013142	SCV004931847	pathogenic	Li-Fraumeni syndrome 1	2024-02-16	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 1631137, 10629033, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 1978757, 23406775].
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	Prostate adenocarcinoma	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	Gastric adenocarcinoma	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