Submissions for variant NM_000546.5(TP53):c.818G>T (p.Arg273Leu) (rs28934576)

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000568814	SCV000665156	pathogenic	Hereditary cancer-predisposing syndrome	2018-10-11	criteria provided, single submitter	clinical testing	The p.R273L pathogenic mutation (also known as c.818G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 818. The arginine at codon 273 is replaced by leucine, an amino acid with dissimilar properties. This mutation occurs at a well-characterized mutation "hotspot" located within the functionally critical DNA binding domain. Several other mutations have been described at this position and are associated with a classic LFS-associated tumor spectrum (Petitjean A et al. IARC TP53 database [version R16, November 2012]. Hum Mutat. 2007 Jun;28(6):622-9). This specific alteration has been reported in a family meeting Chompret criteria for Li-Fraumeni Syndrome, and has been identified as a de novo mutation in a patient diagnosed with adrenaocortical carcinoma and rhabdomyosarcoma at 1 year of age (Bougeard Get al. J. Clin. Oncol. 2015 Jul; 33(21):2345-52; Chompret A et al. Br. J. Cancer 2000 Jun; 82(12):1932-7). Functional assays conducted in both yeast and human cells have shown a loss of transactivation capacity and a dominant negative phenotype (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti, P et al. Mol Cancer Res. 2011 Mar;9(3):271-9; Dearth Let al. Carcinogenesis 2007 Feb; 28(2):289-98). 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 crystal structure analysis, this position has been shown to be involved in DNA contact and binding (Martin A et al. Hum. Mutat. 2002 Feb; 19(2):149-64). Based on the available evidence, p.R273L is classified as a pathogenic mutation.
Invitae	RCV000822080	SCV000962866	pathogenic	Li-Fraumeni syndrome	2020-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with leucine at codon 273 of the TP53 protein (p.Arg273Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs28934576, ExAC 0.002%). This variant has been observed in individuals affected with Li-Fraumeni-associated cancers (PMID: 10864200, 26014290). In one of this individuals the variant was observed to be de novo (PMID: 10864200). ClinVar contains an entry for this variant (Variation ID: 376655). This variant has been reported to affect TP53 protein function (PMID: 12826609, 30224644, 29979965, 9407971, 21343334). This variant disrupts the p.273 amino acid residue in TP53. Other variants that disrupt this residue have been observed in affected individuals (PMID: 9242456, 21484931, 17540308, 1565144, 20693561, 21552135), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001539823	SCV001757640	pathogenic	not provided	2020-06-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of apoptotic activity, and exhibits a dominant-negative effect (Monti et al., 2007; Monti et al., 2011; Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 10864200, 26014290, 21343334, 17606709, 29979965, 15510160, 17311302, 29092957, 29752319, 30720243, 9407971, 30840781)
Database of Curated Mutations (DoCM)	RCV000423981	SCV000509434	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434695	SCV000509435	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444989	SCV000509436	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427314	SCV000509437	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437048	SCV000509438	likely pathogenic	Adenocarcinoma of stomach	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444109	SCV000509439	likely pathogenic	Ovarian Serous Cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426132	SCV000509440	likely pathogenic	Adrenocortical carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436818	SCV000509441	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418738	SCV000509442	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429444	SCV000509443	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435767	SCV000509444	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418536	SCV000509445	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428692	SCV000509446	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438507	SCV000509447	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421259	SCV000509448	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431067	SCV000509449	likely pathogenic	Adenocarcinoma of prostate	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441792	SCV000509450	likely pathogenic	Uterine Carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423633	SCV000509451	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434296	SCV000509452	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442241	SCV000509453	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423490	SCV000509454	likely pathogenic	Chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433315	SCV000509455	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444782	SCV000509456	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425890	SCV000509457	likely pathogenic	Medulloblastoma	2016-05-31	no assertion criteria provided	literature only
Genome Sciences Centre, British Columbia Cancer Agency	RCV000515526	SCV000611151	likely pathogenic	Metastatic pancreatic neuroendocrine tumours	2017-11-01	no assertion criteria provided	research
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne	RCV000785524	SCV000924096	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research