Submissions for variant NM_000546.6(TP53):c.638G>C (p.Arg213Pro)

dbSNP: rs587778720

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220461	SCV000274991	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-12	criteria provided, single submitter	clinical testing	The p.R213P pathogenic mutation (also known as c.638G>C), located in coding exon 5 of the TP53 gene, results from a G to C substitution at nucleotide position 638. The arginine at codon 213 is replaced by proline, an amino acid with dissimilar properties. This alteration was first described segregating with disease in a family satisfying clinical criteria for classic Li-Fraumeni syndrome (LFS) (Dockhorn-Dworniczak B et al, Eur. J. Cancer 1996 Jul; 32A(8):1359-65). Tumor analyses from p.R213P-carriers in this family revealed increased nuclear p53 staining as well as somatic loss-of-heterozygosity (LOH). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (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 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). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al., Science 1994 Jul; 265(5170):346-55). In addition, another alteration at the same codon, p.R213Q, has been identified in multiple suspected-LFS patients and is considered pathogenic (Achatz MI et al. Cancer Lett. 2007 Jan 8;245(1-2):96-102; Becherini et al. Neuropathol Appl Neurobiol. 2008 Oct;34(5):564-8; Ruijs MW et al. J Med Genet. 2010 Jun;47(6):421-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506128	SCV000605421	likely pathogenic	not specified	2016-11-02	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000220461	SCV002582373	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288865	SCV002583034	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Invitae	RCV002518297	SCV003442486	pathogenic	Li-Fraumeni syndrome	2023-09-09	criteria provided, single submitter	clinical testing	This variant is also known as CGA to CCA transversion. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg213 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 6736287, 16494995, 17541742, 18208484, 19468865, 20522432, 23259501). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 231214). This missense change has been observed in individual(s) with Li-Fraumeni Syndrome (PMID: 8869100). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 213 of the TP53 protein (p.Arg213Pro).
Database of Curated Mutations (DoCM)	RCV000429975	SCV000509240	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440212	SCV000509241	likely pathogenic	Nasopharyngeal neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423147	SCV000509242	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433848	SCV000509243	likely pathogenic	Adrenal cortex carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441029	SCV000509244	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423776	SCV000509245	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434458	SCV000509246	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443850	SCV000509247	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424407	SCV000509248	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431639	SCV000509249	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443926	SCV000509250	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425014	SCV000509251	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435742	SCV000509252	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418520	SCV000509253	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426111	SCV000509254	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436779	SCV000509255	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419521	SCV000509256	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430230	SCV000509257	likely pathogenic	Adenoid cystic carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440917	SCV000509258	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420213	SCV000509259	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430895	SCV000509260	likely pathogenic	Papillary renal cell carcinoma type 1	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441598	SCV000509261	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only