Submissions for variant NM_000546.6(TP53):c.641A>G (p.His214Arg)

dbSNP: rs1057519992

Total submissions: 17

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	2022-06-27	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	likely pathogenic	Li-Fraumeni syndrome	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 214 of the TP53 protein (p.His214Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 20522432; external communication). ClinVar contains an entry for this variant (Variation ID: 376615). 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: 7732013, 9546439, 10761705, 11920959, 12826609, 30224644). 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.
Ambry Genetics	RCV000492372	SCV000581129	pathogenic	Hereditary cancer-predisposing syndrome	2020-11-17	criteria provided, single submitter	clinical testing	The p.H214R pathogenic mutation (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 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 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; 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). 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 has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000492372	SCV001358774	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-14	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 214 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). Experimental studies have shown that this variant results in protein that is non-functional in yeast transactivation assays (PMID: 12826609, 20407015), human cell growth suppression assays (PMID: 30224644), and human cell proliferation assay (PMID: 29979965). This variant has been reported in a 41 year old Dutch individual affected with Li Fraumeni-like syndrome meeting Chompret criteria (PMID: 20522432) and a 3 year old Chinese individual affected with glioma (PMID: 35033608). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
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)
CeGaT Center for Human Genetics Tuebingen	RCV001584113	SCV002822356	pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000445232	SCV000508586	likely pathogenic	B-cell chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427653	SCV000508587	likely pathogenic	Gastric adenocarcinoma	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	Papillary renal cell carcinoma type 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