Submissions for variant NM_000546.6(TP53):c.817C>G (p.Arg273Gly)

dbSNP: rs121913343

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814073	SCV000954470	pathogenic	Li-Fraumeni syndrome	2021-09-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg273 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1565144, 8164043, 8479749, 17606709, 18685109, 20693561, 21535297, 21552135, 25584008; Invitae). 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: 12826609, 17606709, 21343334). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with bilateral breast cancer and rhabdomyosarcoma, acute lymphoblastic leukaemia and gestational choriocarcinoma (PMID: 8425176, 25612911, 29070607). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 273 of the TP53 protein (p.Arg273Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine.
Ambry Genetics	RCV001027249	SCV001189776	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-22	criteria provided, single submitter	clinical testing	The p.R273G pathogenic mutation (also known as c.817C>G), located in coding exon 7 of the TP53 gene, results from a C to G substitution at nucleotide position 817. The arginine at codon 273 is replaced by glycine, an amino acid with dissimilar properties. This alteration occurs at a well-characterized mutation "hotspot" located within the functionally critical DNA binding domain, and has been seen in a classic LFS pedigree with early onset breast cancer and hematopoietic and nervous system malignancies (Brugières L et al. Cancer Res. 1993 Feb;53(3):452-5). This alteration has also been confirmed de novo in an individual with bilateral breast cancers diagnosed at age 26, and reported in a pediatric patient with a personal history of rhabdomyosarcoma, osteosarcoma, and brain cancer (Renaux-Petel M et al. J Med Genet, 2018 03;55:173-180; Pondrom M et al. Pediatr Blood Cancer, 2020 09;67:e28486). This alteration is reported to have loss of transactivation capacity and a dominant negative effect in yeast based assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9; Li J et al. Hum. Mutat. 2014 May; 35(5):575-84). 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). 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.
Genome-Nilou Lab	RCV001027249	SCV002582453	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002290030	SCV002583115	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002487616	SCV002793918	pathogenic	Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma; Colorectal cancer; Bone marrow failure syndrome 5	2022-04-10	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002290030	SCV004930549	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-20	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 29070607, 8425176].
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785275	SCV000923843	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research