Submissions for variant NM_000546.6(TP53):c.535C>G (p.His179Asp)

dbSNP: rs587780070

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001851020	SCV002230464	pathogenic	Li-Fraumeni syndrome	2023-08-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His179 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11896595, 12509279, 12726864, 12826609, 16633321, 17530187, 18511570, 25433984, 26497680). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). 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. ClinVar contains an entry for this variant (Variation ID: 376610). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 32658383; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 179 of the TP53 protein (p.His179Asp).
Ambry Genetics	RCV002348144	SCV002645091	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-02	criteria provided, single submitter	clinical testing	The p.H179D variant (also known as c.535C>G), located in coding exon 4 of the TP53 gene, results from a C to G substitution at nucleotide position 535. The histidine at codon 179 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported as a de novo alteration in a male with no tumor history from a cohort of known TP53 mutation carriers (Renaux-Petel M et al. J. Med. Genet., 2018 03;55:173-180). This alteration has also been reported in a patient with a personal history of rhabdomyosarcoma of embryonal anaplastic subtype diagnosed at age 3 (Pondrom M et al. Pediatr Blood Cancer, 2020 Sep;67:e28486). This variant is in the DNA binding domain of the TP53 protein and is reported to have partial loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Additional 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). In addition, other alterations at this same position, p.H179Q (c.537T>A) and p.H179Q (c.537T>G), have been identified as de novo and/or in patients with features suggestive of Li-Fraumeni or Li-Fraumeni-like syndrome (Bougeard G et al. J Med Genet. 2008 Aug;45(8):535-8; Gonzalez KD et al. J. Med. Genet. 2009 Oct; 46(10):689-93; Sheng S et al. Int. J. Cancer, 2020 01;146:487-495). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465649	SCV002760884	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003335320	SCV004045022	pathogenic	Li-Fraumeni syndrome 1	2023-06-13	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21590121, 29070607, 32658383].
Baylor Genetics	RCV003470376	SCV004206262	likely pathogenic	Adrenocortical carcinoma, hereditary	2023-07-02	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000440707	SCV000508428	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423899	SCV000508429	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430612	SCV000508430	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441771	SCV000508431	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424030	SCV000508432	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431709	SCV000508433	likely pathogenic	Gallbladder carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444992	SCV000508434	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421694	SCV000508435	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431956	SCV000508436	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444860	SCV000508437	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425288	SCV000508438	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436443	SCV000508439	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443866	SCV000508440	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426383	SCV000508441	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436622	SCV000508442	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419821	SCV000508443	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430072	SCV000508444	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437679	SCV000508445	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420116	SCV000508446	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only