Submissions for variant NM_000546.5(TP53):c.535C>T (p.His179Tyr) (rs587780070)

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000663095	SCV000786200	likely pathogenic	Li-Fraumeni syndrome 1	2018-03-16	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000424007	SCV000508352	likely pathogenic	Small cell lung cancer	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434725	SCV000508353	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444364	SCV000508354	likely pathogenic	Neoplasm of the breast	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427283	SCV000508355	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435360	SCV000508356	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444227	SCV000508357	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424716	SCV000508358	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436304	SCV000508359	likely pathogenic	Uterine Carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419024	SCV000508360	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428854	SCV000508361	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436095	SCV000508362	likely pathogenic	Carcinoma of gallbladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419735	SCV000508363	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430411	SCV000508364	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440222	SCV000508365	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423020	SCV000508366	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431087	SCV000508367	likely pathogenic	Ovarian Serous Cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441827	SCV000508368	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423688	SCV000508369	likely pathogenic	Adenocarcinoma of stomach	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434379	SCV000508370	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
GeneDx	RCV000115726	SCV000149635	pathogenic	not provided	2014-02-06	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.535C>T at the cDNA level, p.His179Tyr (H179Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAT>TAT) in exon 5. This mutation has been observed as a somatic mutation in over 100 different cancers but has only been observed as a germline mutation in one patient with a history of six cancers, most being classic Li-Fraumeni tumors: fibrosarcoma, adrenal cortical carcinoma, osteosarcoma, ductal carcinoma in situ, infiltrating ductal carcinoma and adenocarcinoma of the pancreas (IARC TP53 Database, Lefrou 2006). Two in vitro functional assays have shown that this mutation has similar protein activity as cells null for the p53 protein (Ko 2002, Yang 2007). TP53 His179Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Variant Server, indicating it is not a common benign variant in these populations. This mutation is a non-conservative substitution in which a positive polar amino acid is replaced with a neutral polar one, altering a position that is well conserved throughout evolution and is located in within the DNA-binding domain and the region that interacts with HIPK1, ZNF385A, FBX042 and AXIN1. Based on the currently available information, we consider TP53 His179Tyr to be a pathogenic mutation This variant has been seen apparently mosaic. The variant is found in BR-OV-HEREDIC panel(s).
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne	RCV000785312	SCV000923880	likely pathogenic	Ovarian Neoplasms	2018-12-01	no assertion criteria provided	research
Invitae	RCV000555493	SCV000629834	pathogenic	Li-Fraumeni syndrome	2017-09-12	criteria provided, single submitter	clinical testing	This sequence change replaces histidine with tyrosine at codon 179 of the TP53 protein (p.His179Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with a personal and/or family history of Li-Fraumeni syndrome, including one individual in whom it was reported to arise de novo (PMID: 16633321, 18511570, 25433984). ClinVar contains an entry for this variant (Variation ID: 127815). Experimental studies in cell lines and yeast have shown that this missense change disrupts TP53 protein function and acts in a dominant-negative manner (PMID: 12509279, 17530187, 12826609, 26497680, 12726864, 11896595). For these reasons, this variant has been classified as Pathogenic.