Submissions for variant NM_000546.6(TP53):c.743G>T (p.Arg248Leu)

dbSNP: rs11540652

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000991149	SCV001142561	pathogenic	Li-Fraumeni syndrome	2019-08-28	reviewed by expert panel	curation	This variant is within a codon that is an established hotspot in the TP53 gene (PM1; PMID: 2046748). It is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has been reported in 1 family meeting classic Li-Fraumeni syndrome and 1 proband meeting Chompret criteria (PS4_Supporting; PMID: 1359493, 25584008). In summary, TP53 c.743G>T; p.Arg248Leu meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM1, PM2_Supporting, PP3_Moderate, PS3, PS4_Supporting.
Ambry Genetics	RCV000219834	SCV000273723	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-12	criteria provided, single submitter	clinical testing	The p.R248L pathogenic mutation (also known as c.743G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at nucleotide position 743. The arginine at codon 248 is replaced by leucine, an amino acid with dissimilar properties. This variant has been reported in a cohort of Chinese individuals at an high risk for breast cancer (Li JY et al. Int J Cancer, 2019 Jan;144:281-289). 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 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 U S A, 2003 Jul;100:8424-9; Dearth LR et al. Carcinogenesis, 2007 Feb;28:289-98; Jordan JJ et al. Mol Cancer Res, 2010 May;8:701-16). 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 alteration is located at a position or in a region that is critical for protein function (Ambry internal data). 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.
Invitae	RCV000991149	SCV001392992	likely pathogenic	Li-Fraumeni syndrome	2023-06-16	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 9290701, 12826609, 20407015, 25584008). 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: 230253). This missense change has been observed in individual(s) with breast cancer (PMID: 29752822). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 248 of the TP53 protein (p.Arg248Leu).
Color Diagnostics, LLC DBA Color Health	RCV000219834	SCV002052387	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 248 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein is non-functional in transactivation assay (PMID: 12826609, 25584008, 29786075) and in human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in individuals affected with Li-Fraumeni syndrome (PMID: 1359493), adrenocortical carcinoma (PMID 25584008) and early-onset breast cancer (PMID: 29752822). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same codon, p.Arg248Gln and p.Arg248Trp, are known to be disease-causing (Clinvar variation ID: 12356 and 12347), indicating that arginine at this position is important for TP53 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Baylor Genetics	RCV003475005	SCV004204257	likely pathogenic	Adrenocortical carcinoma, hereditary	2023-03-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004020650	SCV004933545	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: 29979965, 8062826, 25584008]. This variant is expected to disrupt protein structure [Myriad internal data].
Database of Curated Mutations (DoCM)	RCV000439516	SCV000509284	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422303	SCV000509285	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433237	SCV000509286	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445266	SCV000509287	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423159	SCV000509288	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433865	SCV000509289	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443630	SCV000509290	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427307	SCV000509291	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437940	SCV000509292	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443712	SCV000509293	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424394	SCV000509294	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435101	SCV000509295	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417894	SCV000509296	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428586	SCV000509297	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435726	SCV000509298	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418531	SCV000509299	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429221	SCV000509300	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439901	SCV000509301	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422821	SCV000509302	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430044	SCV000509303	likely pathogenic	B-cell chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440686	SCV000509304	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423468	SCV000509305	likely pathogenic	Medulloblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434177	SCV000509306	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445145	SCV000509307	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424119	SCV000509308	likely pathogenic	Myelodysplastic syndrome	2016-05-31	no assertion criteria provided	literature only