Submissions for variant NM_000546.6(TP53):c.743G>C (p.Arg248Pro)

dbSNP: rs11540652

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000229442	SCV000285211	pathogenic	Li-Fraumeni syndrome	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 248 of the TP53 protein (p.Arg248Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Li-Fraumeni syndrome associated tumors (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 237954). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 8062826, 9546439, 12826609, 15722483). This variant disrupts the p.Arg248 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18511570, 19556618, 20128691). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002378977	SCV002672589	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-03	criteria provided, single submitter	clinical testing	The p.R248P variant (also known as c.743G>C), located in coding exon 6 of the TP53 gene, results from a G to C substitution at nucleotide position 743. The arginine at codon 248 is replaced by proline, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9, Flaman J et al., Oncogene 1998 Mar; 16(10):1369-72). Additional studies showed that although this alteration produced a protein with normal conformation, it was unable to activate transcription, bind linear DNA, or inhibit cell proliferation (Ory K et al., EMBO J. 1994 Aug; 13(15):3496-504; Göhler T et al., Nucleic Acids Res. 2005 ; 33(3):1087-100). Although this exact variant has not been reported in the literature, several other alterations at this same codon (p.R248Q, p.R248W and p.R248L) have been reported in Li-Fraumeni Syndrome, or LFS related cancers (Petitjean A et al. IARC TP53 database [version R15, November 2010]. Hum Mutat. 2007 Jun;28(6):622-9; Rausch T et al., Cell 2012 Jan; 148(1-2):59-71; Toguchida J et al., N. Engl. J. Med. 1992 May; 326(20):1301-8; Rieber J et al., Genes Chromosomes Cancer 2009 Jul; 48(7):558-68). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Cho Y et al., Science 1994 Jul; 265(5170):346-55). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV004020765	SCV004932085	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-16	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 8062826, 8023157, 17417627, 14743206, 9150393]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10089074, 9242456, 15381368, 1565143, 20522432].
Database of Curated Mutations (DoCM)	RCV000434831	SCV000509309	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445077	SCV000509310	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424795	SCV000509311	likely pathogenic	Myelodysplastic syndrome	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435488	SCV000509312	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444130	SCV000509313	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425414	SCV000509314	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436124	SCV000509315	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418894	SCV000509316	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426089	SCV000509317	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436850	SCV000509318	likely pathogenic	Medulloblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419610	SCV000509319	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430314	SCV000509320	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441018	SCV000509321	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420292	SCV000509322	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430964	SCV000509323	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441674	SCV000509324	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420936	SCV000509325	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431663	SCV000509326	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438849	SCV000509327	likely pathogenic	B-cell chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421633	SCV000509328	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432304	SCV000509329	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444805	SCV000509330	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425773	SCV000509331	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432999	SCV000509332	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443867	SCV000509333	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only