ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs587780070
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Total submissions: 28
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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

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