Submissions for variant NM_000546.6(TP53):c.581T>A (p.Leu194His)

dbSNP: rs1057519998

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000565549	SCV000664789	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-29	criteria provided, single submitter	clinical testing	The p.L194H variant (also known as c.581T>A), located in coding exon 5 of the TP53 gene, results from a T to A substitution at nucleotide position 581. The leucine at codon 194 is replaced by histidine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity, dominant negative effect and predicted to affect several p53 isoforms in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Waddell S, et al. Oncogene 2001 Sep; 20(42):6001-8).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV001376885	SCV001574071	likely pathogenic	Li-Fraumeni syndrome	2020-07-10	criteria provided, single submitter	clinical testing	This variant disrupts the p.Leu194 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9572492, 12826609, 18818522, 29979965, 30224644, 21761402, 27501770, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has been reported to affect TP53 protein function (PMID: 30224644, 29979965, 12826609). This sequence change replaces leucine with histidine at codon 194 of the TP53 protein (p.Leu194His). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 376634).
Database of Curated Mutations (DoCM)	RCV000422209	SCV000508847	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431615	SCV000508848	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443173	SCV000508849	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421586	SCV000508850	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431831	SCV000508851	likely pathogenic	Neoplasm of uterine cervix	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443531	SCV000508852	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427064	SCV000508853	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434795	SCV000508854	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442619	SCV000508855	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426499	SCV000508856	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436747	SCV000508857	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785543	SCV000924115	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research