Submissions for variant NM_000546.6(TP53):c.523C>G (p.Arg175Gly)

dbSNP: rs138729528

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000459914	SCV000545325	pathogenic	Li-Fraumeni syndrome	2023-08-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg175 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8164043, 8825920, 15607980, 15607981, 16401470, 21761402, 22006311, 23263379, 23792586). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TP53 function (PMID: 8062826, 9546439, 12007217, 12826609, 20516128, 21343334, 23263379, 24573247). 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. ClinVar contains an entry for this variant (Variation ID: 376649). This missense change has been observed in individual(s) with Li-Fraumeni syndrome and hereditary breast and/or ovarian cancer (PMID: 11370630, 17606709, 25927356). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 175 of the TP53 protein (p.Arg175Gly).
Ambry Genetics	RCV000573315	SCV000664381	pathogenic	Hereditary cancer-predisposing syndrome	2019-08-21	criteria provided, single submitter	clinical testing	The p.R175G pathogenic mutation (also known as c.523C>G), located in coding exon 4 of the TP53 gene, results from a C to G substitution at nucleotide position 523. The arginine at codon 175 is replaced by glycine, an amino acid with dissimilar properties. This alteration was identified in a French family meeting Li-Fraumeni syndrome criteria, where the proband had osteosarcoma at 18, and two primary breast cancers at 27 and 29 (Bougeard G et al. J. Med. Genet., 2001 Apr;38:253-7). Multiple functional studies in both yeast and mammalian cells have shown a loss of transactivation activity for this variant (Monti P et al. Mol. Cancer Res., 2011 Mar;9:271-9; Ory K et al. EMBO J., 1994 Aug;13:3496-504; Flaman JM et al. Oncogene, 1998 Mar;16:1369-72; IARC TP53 database: Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Zerdoumi Y et al. Hum. Mol. Genet., 2017 07;26:2591-2602). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). In addition, another alteration at this same amino acid position (p.R175H) is a well characterized TP53 hotspot mutation (Soussi T et al. Cell Death Differ., 2015 Aug;22:1239-49). This amino acid position is highly conserved in available vertebrate species, and is predicted to be deleterious by in silico analysis. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV001584115	SCV001820208	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression activity (Ory et al., 1994; Flaman et al., 1998; Kato et al., 2003; Zerdoumi et al., 2017; Giacomelli et al., 2081; Kotler et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21343334, 25927356, 8062826, 12826609, 28472496, 11370630, 17606709, 16707427, 34426522, 35022142, 15510160, 28369373, 9546439, 26619011, 30661751, 14559903, 30720243, 30840781, 31105275, 32658383, 34273903, 30224644, 29979965, 11332399)
Genome-Nilou Lab	RCV000573315	SCV002582494	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289532	SCV002583156	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000424235	SCV000509136	likely pathogenic	Nasopharyngeal neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430584	SCV000509137	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441260	SCV000509138	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421436	SCV000509139	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432105	SCV000509140	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444111	SCV000509141	likely pathogenic	B-cell chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421238	SCV000509142	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432831	SCV000509143	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444080	SCV000509144	likely pathogenic	Gallbladder carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425355	SCV000509145	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436078	SCV000509146	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443278	SCV000509147	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426938	SCV000509148	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436759	SCV000509149	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419625	SCV000509150	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430740	SCV000509151	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437498	SCV000509152	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420706	SCV000509153	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430935	SCV000509154	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438570	SCV000509155	likely pathogenic	Medulloblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420923	SCV000509156	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428548	SCV000509157	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785486	SCV000924058	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research