Submissions for variant NM_000546.5(TP53):c.641A>G (p.His214Arg) (rs1057519992)

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen	RCV000477234	SCV001142540	likely pathogenic	Li-Fraumeni syndrome	2019-08-28	reviewed by expert panel	curation	This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). 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 >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Additionally, this variant has been reported in 2 probands meeting Chompret criteria (PS4_Supporting; PMID: 20522432, ClinVar SCV000581129.3). In summary, TP53 c.641A>G; p.His214Arg meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PS3, PM1, PS4_Supporting.
Invitae	RCV000477234	SCV000545273	uncertain significance	Li-Fraumeni syndrome	2020-09-24	criteria provided, single submitter	clinical testing	This sequence change replaces histidine with arginine at codon 214 of the TP53 protein (p.His214Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with Li-Fraumeni syndrome (PMID: 20522432). ClinVar contains an entry for this variant (Variation ID: 376615). Experimental studies have shown that this missense change impacts protein function (PMID: 12826609, 9546439, 7732013, 10761705, 11920959, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000492372	SCV000581129	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-02-19	criteria provided, single submitter	clinical testing	The p.H214R variant (also known as c.641A>G), located in coding exon 5 of the TP53 gene, results from an A to G substitution at nucleotide position 641. The histidine at codon 214 is replaced by arginine, an amino acid with highly similar properties. This alteration is located in the DNA binding domain and has been shown to be temperature sensitive, and have a loss of transactivation capability in yeast-based functional studies (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Yamamoto S et al. Jpn. J. Cancer Res. 2000 Feb; 91(2):181-9; Flaman JM et al. Oncogene 1998 Mar; 16(10):1369-72). This variant was detected in an individual meeting Chompret criteria with breast cancer at 35, brain cancer at 40, and adrenocortical carcinoma at 41 (Ruijs MW et al. J. Med. Genet. 2010 Jun; 47(6):421-8). This amino acid position is highly conserved through mammals on sequence alignment. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc	RCV000492372	SCV001358774	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-09-08	criteria provided, single submitter	clinical testing
GeneDx	RCV001584113	SCV001818487	likely pathogenic	not provided	2019-09-17	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33300245, 31105275, 30720243, 30840781, 30224644, 31394872, 29979965, 20407015, 25584008, 24651012, 23772609, 8242631, 24510342, 26682952, 11920959, 20522432, 26053092, 16337994, 21197471, 25710373, 20436704, 26425688, 23196062, 28137276, 26066407, 18689542, 25916844, 26331835, 21232794, 19020536, 23967324, 24523142, 9546439, 7732013, 10761705, 14559903, 9290701, 29707145)
Database of Curated Mutations (DoCM)	RCV000445232	SCV000508586	likely pathogenic	Chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427653	SCV000508587	likely pathogenic	Adenocarcinoma of stomach	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434864	SCV000508588	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417658	SCV000508589	likely pathogenic	Renal cell carcinoma, papillary, 1	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428396	SCV000508590	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435583	SCV000508591	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418330	SCV000508592	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429028	SCV000508593	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439733	SCV000508594	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422504	SCV000508595	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429736	SCV000508596	likely pathogenic	Ovarian Serous Cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only