Submissions for variant NM_000546.6(TP53):c.844C>G (p.Arg282Gly)

dbSNP: rs28934574

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129010	SCV000172907	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-28	criteria provided, single submitter	clinical testing	The p.R282G pathogenic mutation (also known as c.844C>G), located in coding exon 7 of the TP53 gene, results from a C to G substitution at nucleotide position 844. The arginine at codon 282 is replaced by glycine, an amino acid with dissimilar properties. This mutation is in the DNA binding domain of the p53 protein and is reported to have loss of transactivation capacity and predicted to affect several p53 isoforms (IARC TP53 database; 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 (Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). It was previously identified in a patient with primary orbital liposarcoma whose family met diagnostic criteria for Li-Fraumeni syndrome (LFS) (Poli T et al. Tumori; 91:96-100). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Additionally, two other missense mutations occurring at the same codon have been reported (p.R282Q and p.R282W). In one study, the p.R282Q mutation was reported in a 14-year-old male with a soft tissue sarcoma who was later diagnosed with an osteosarcoma and lung cancer (Chompret et al. 2000 British J Cancer 82(12):1932-1937). The p.R282W mutation was detected in a patient with contralateral breast cancer at age 32 (Heyman et al. 2010 Radiation Oncology 5:104), and in a kindred with clinical LFS, however, specific clinical information was not provided (Wu et al. 2011 Hum Genet 129:663-673). Based on the supporting evidence, the p.R282G alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380073	SCV001578015	pathogenic	Li-Fraumeni syndrome	2023-04-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 282 of the TP53 protein (p.Arg282Gly). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg282 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1565143, 1565144, 11370630, 12826609, 17606709, 19468865, 21305319, 21761402, 22672556, 25584008). 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, 21343334, 23246812, 29979965, 30224644). 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: 140821). This missense change has been observed in individuals with clinical features of Li-Fraumeni Syndrome (PMID: 15850016, 26014290, 26556299, 28802053). This variant is not present in population databases (gnomAD no frequency).
Genome-Nilou Lab	RCV000129010	SCV002582449	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288620	SCV002583111	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001380073	SCV005203953	pathogenic	Li-Fraumeni syndrome	2024-06-24	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.844C>G (p.Arg282Gly) results in a non-conservative amino acid change located in the DNA-binding domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251410 control chromosomes (gnomAD). c.844C>G has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (LFS) and tumors belonging to the LFS spectrum (e.g. Poli_2005, Bougeard_2008, Schrader_2016, Rana_2019, Ceyhan-Birsoy_2021). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.844C>T, p.R282W), supporting the critical relevance of codon 282 to TP53 protein function. Multiple publications also reported experimental evidence and demonstrated the variant to be non-functional based on transcriptional activity in yeast, and substantially affecting TP53 function in human cell lines (e.g. Kato_2003, Monti_2011, Giacomelli_2018). The following publications have been ascertained in the context of this evaluation (PMID: 30224644, 15850016, 18511570, 26556299, 31105275, 34240179, 12826609). ClinVar contains an entry for this variant (Variation ID: 140821). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV004719707	SCV005324863	pathogenic	not provided	2023-05-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression activity (Monti et al., 2003; Ferrone et al., 2006; Giacomelli et al., 2018; Kotler et al., 2018); Observed in individuals with TP53-related tumors (Bougeard et al., 2015; Pelttari et al., 2017; Rana et al., 2019; Gao et al., 2020); 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, 22672556, 21761402, 21059199, 26619011, 25584008, 29979965, 11370630, 16818505, 12826609, 21305319, 12917626, 30224644, 1565144, 15850016, 23246812, 19468865, 17606709, 1565143, 15510160, 26556299, 30840781, 31105275, 32817165, 26014290, 22768918, 30720243, 28802053, 25847421)
Database of Curated Mutations (DoCM)	RCV000440446	SCV000509593	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422747	SCV000509594	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430393	SCV000509595	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440653	SCV000509596	likely pathogenic	Papillary renal cell carcinoma type 1	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422134	SCV000509597	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432433	SCV000509598	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442627	SCV000509599	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422367	SCV000509600	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431764	SCV000509601	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442540	SCV000509602	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425179	SCV000509603	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435503	SCV000509604	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445294	SCV000509605	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427647	SCV000509606	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437895	SCV000509607	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419333	SCV000509608	likely pathogenic	Non-Hodgkin lymphoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430047	SCV000509609	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437219	SCV000509610	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419993	SCV000509611	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785299	SCV000923867	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research