Submissions for variant NM_000546.6(TP53):c.536A>C (p.His179Pro)

dbSNP: rs1057519991

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001023982	SCV001185931	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-03-19	criteria provided, single submitter	clinical testing	The p.H179P variant (also known as c.536A>C), located in coding exon 4 of the TP53 gene, results from an A to C substitution at nucleotide position 536. The histidine at codon 179 is replaced by proline, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have partial loss of transactivation capacity (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). The amino acid residue altered by this variant has been shown to be functionally important for zinc binding, and alterations affecting this amino acid have been associated with poorer prognosis in breast cancer patients (Martin AC et al. Hum. Mutat., 2002 Feb;19:149-64; Olivier M et al. Clin. Cancer Res., 2006 Feb;12:1157-67). 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). This amino acid position is highly conserved in available vertebrate species. 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.
Invitae	RCV001861483	SCV002213697	uncertain significance	Li-Fraumeni syndrome	2021-10-04	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 376611). This missense change has been observed in individual(s) with early onset breast cancer (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with proline at codon 179 of the TP53 protein (p.His179Pro). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and proline.
Database of Curated Mutations (DoCM)	RCV000431234	SCV000508447	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441519	SCV000508448	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421224	SCV000508449	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427925	SCV000508450	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439058	SCV000508451	likely pathogenic	Gallbladder carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421433	SCV000508452	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432547	SCV000508453	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444604	SCV000508454	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422328	SCV000508455	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433456	SCV000508456	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444694	SCV000508457	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426919	SCV000508458	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437164	SCV000508459	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443703	SCV000508460	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427172	SCV000508461	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438275	SCV000508462	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420510	SCV000508463	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428125	SCV000508464	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434884	SCV000508465	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only