Submissions for variant NM_000546.6(TP53):c.535C>T (p.His179Tyr)

gnomAD frequency: 0.00001  dbSNP: rs587780070

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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).
Invitae	RCV000555493	SCV000629834	pathogenic	Li-Fraumeni syndrome	2023-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 179 of the TP53 protein (p.His179Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of Li-Fraumeni syndrome (PMID: 16633321, 18511570, 25433984). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 127815). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 11896595, 12509279, 12726864, 12826609, 17530187, 26497680). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000663095	SCV000786200	likely pathogenic	Li-Fraumeni syndrome 1	2018-03-16	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288597	SCV002582383	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000663095	SCV002583045	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002288597	SCV002647112	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-13	criteria provided, single submitter	clinical testing	The p.H179Y pathogenic mutation (also known as c.535C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 535. The histidine at codon 179 is replaced by tyrosine, an amino acid with similar properties. This mutation has been reported in the germline of multiple individuals with Li-Fraumeni syndrome (Lefrou L et al. Gastroenterol. Clin. Biol., 2006 Mar;30:484-6; Bougeard G et al. J. Clin. Oncol., 2015 Jul;33:2345-52; Zerdoumi Y et al. Hum. Mol. Genet., 2017 Jul;26:2591-2602). Numerous functional assays conducted in yeast and mammalian cells have shown the p.Y179H variant has decreased transactivation activity compared to wild type, and exerts a dominant negative effect (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9, Dearth LR et al. Carcinogenesis 2007 Feb; 28(2):289-98; Scian MJ et al. Oncogene, 2004 May;23:4430-43). Further functional studies indicate this mutation has oncogenic properties through upregulation of genes involved in cell cycle progression and proliferation (Ko JL et al. DNA Repair Amst; Yang D et al. Mol. Cell. Biochem., 2007 Oct;304:219-26; Scian MJ et al. Oncogene, 2004 May;23:4430-43). 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 in the DNA binding domain, and is one of four residues necessary to bind the zinc molecule that stabilizes the beta sheet structure of the p53 protein (Martin AC et al. Hum. Mutat. 2002 Feb; 19(2):149-64). 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). In addition, another alteration at this same position, p.H179Q was identified as a de novo mutation in a patient with two Li-Fraumeni core cancers (Gonzalez KD et al. J. Med. Genet. 2009 Oct; 46(10):689-93). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV000663095	SCV004017964	pathogenic	Li-Fraumeni syndrome 1	2023-04-13	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16633321]. Functional studies indicate this variant impacts protein function [PMID: 12509279, 17530187]. This variant is expected to disrupt protein structure [Myriad internal data].
Baylor Genetics	RCV003460828	SCV004206243	pathogenic	Adrenocortical carcinoma, hereditary	2023-08-17	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000424007	SCV000508352	likely pathogenic	Small cell lung carcinoma	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	Breast neoplasm	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	Gallbladder carcinoma	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	Gastric adenocarcinoma	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
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785312	SCV000923880	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research