Submissions for variant NM_000546.6(TP53):c.637C>T (p.Arg213Ter)

dbSNP: rs397516436

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036532	SCV000060187	pathogenic	Li-Fraumeni syndrome	2013-08-20	criteria provided, single submitter	clinical testing	The Arg213X variant in TP53 has been previously reported in the literature in se veral individuals with features consistent with or a clinical diagnosis of LFS ( Horio 1994, Frebourg 1995, Varley 1999, Vahteristo 2001, Wong 2006, Trahair 2007 , Ferrarini 2011). Varley et al. (1999) also observed loss of heterozygosity for TP53 in an adrenocortical carcinoma tumor from an individual with the germline Arg213X variant. This variant has been well described as a somatic variant in mu ltiple tumor types, including those found as part of LFS (COSMIC). The Arg213X v ariant leads to a premature stop at codon 213. From this DNA sequencing test, we cannot determine the effect this nucleotide change will have on the protein pro duced, but it is predicted to lead to a truncated or absent protein. Therefore, this variant is highly likely to be pathogenic.
GeneDx	RCV000213050	SCV000149639	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: loss of DNA binding and growth suppression activities (Malcikova 2010, Kotler 2018); Not observed at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 11479205, 25525159, 15656799, 24803582, 30309854, 10486318, 28056804, 29655027, 27059324, 29489754, 20128691, 8134126, 21552135, 20658636, 21626334, 22203015, 15099937, 7887414, 16401470, 24220311, 23334668, 24702488, 26681312, 15902285, 28503720, 29351612, 29979965, 30412573, 29354595, 29700339, 29076966, 21225465, 27146902, 26425688, 9667734, 20522432, 29753700, 30720243, 31278746, 27535533, 31105275, 32000721, 30816478)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000036532	SCV000166399	pathogenic	Li-Fraumeni syndrome	2024-10-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg213*) in the TP53 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 7887414, 11479205, 16401470, 16534790, 21552135, 21626334). ClinVar contains an entry for this variant (Variation ID: 43590). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000115730	SCV000186844	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	clinical testing	The p.R213* pathogenic mutation (also known as c.637C>T), located in coding exon 5 of the TP53 gene, results from a C to T substitution at nucleotide position 637. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has previously been reported in an affected individual from a family meeting classic Li-Fraumeni syndrome criteria (Wong P et al. Gastroenterology. 2006 Jan;130(1):73-9). This mutation has also been reported in patients with gastric cancer, breast cancer and medulloblastoma (Horio Y et al. Oncogene. 1994 Apr;9(4):1231-5; Momota H et al. Pediatr. Blood Cancer. 2010 Sep;55(3):577-9; Masciari S et al. Genet. Med. 2011 Jul;13(7):651-7; Rummel SK et al. Breast Cancer Res. Treat. 2017 Aug;164(3):593-601; Waszak SM et al. Lancet Oncol. 2018 Jun;19(6):785-798). In addition this mutation was shown to result in loss of DNA binding compared to wild-type (Malcikova J et al. Biol. Chem. 2010 Feb-Mar;391(2-3):197-205). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036532	SCV000918325	pathogenic	Li-Fraumeni syndrome	2023-03-03	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.637C>T (p.Arg213X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251460 control chromosomes. c.637C>T has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome and related conditions with co-segregation evidence (Example: Frebourg_1995, Trahair_2007, Masciari_2011 etc.). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. A section of an NSCLC with the variant was negative for TP53 staining, suggesting the transcript is a target for nonsense mediated decay (Hashimoto_1999). Another report shows severe decrease in DNA binding (Malcikova_2010). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo	RCV001270263	SCV001450477	pathogenic	Squamous cell carcinoma of the head and neck		criteria provided, single submitter	case-control
Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo	RCV001270264	SCV001450478	pathogenic	Familial cancer of breast		criteria provided, single submitter	case-control
Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo	RCV001270265	SCV001450479	pathogenic	Colorectal cancer		criteria provided, single submitter	case-control
Genome-Nilou Lab	RCV000115730	SCV002582483	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000144672	SCV002583144	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000144672	SCV003804703	pathogenic	Li-Fraumeni syndrome 1	2023-01-12	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4, PM2_SUP
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000213050	SCV004221368	pathogenic	not provided	2022-10-18	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of TP53 protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with Li Fraumeni Syndrome (PMID: 21552135 (2011)), colorectal cancer (PMID: 26425688 (2015), 32000721 (2020)), breast cancer (PMID: 32994724 (2020), 28503720 (2017), 26681312 (2015)), and ovarian cancer (PMID: 27059324 (2016)). The variant has also been reported in individuals with glioma (PMID: 31278746 (2019)) and medulloblastoma (PMID: 29753700 (2018), 29489754 (2018). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV000144672	SCV004933043	pathogenic	Li-Fraumeni syndrome 1	2024-02-15	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000036532	SCV005689590	pathogenic	Li-Fraumeni syndrome	2025-02-04	criteria provided, single submitter	clinical testing	PVS1; PM2_SUP; PS4
Pathway Genomics	RCV000144672	SCV000190005	pathogenic	Li-Fraumeni syndrome 1	2014-07-24	no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785330	SCV000923898	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
University Health Network, Princess Margaret Cancer Centre	RCV001270264	SCV001738504	pathogenic	Familial cancer of breast	2021-03-19	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000115730	SCV002589030	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-26	no assertion criteria provided	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV004797593	SCV005419152	pathogenic	TP53-related disorder	2024-10-01	no assertion criteria provided	clinical testing