Submissions for variant NM_000546.6(TP53):c.536A>T (p.His179Leu)

dbSNP: rs1057519991

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000705316	SCV000834307	uncertain significance	Li-Fraumeni syndrome	2021-07-08	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with leucine at codon 179 of the TP53 protein (p.His179Leu). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and leucine. This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 376608). Experimental studies have shown that this missense change impairs transcriptional transactivation activity of the TP53 protein, reduces apoptosis activity and confers cisplatin-sensitivity and increased cell mobility to cells carrying this variant, and acts in a dominant-negative fashion to inhibit function of wild-type protein (PMID: 12826609, 16861262, 22114072, 23713777). In addition, cells carrying this variant transplanted in mice induce tumor formation more rapidly than cells carrying wild-type TP53 (PMID: 9049183). 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. Variants that disrupt the 179 amino acid residue in TP53 have been observed in affected individuals (PMID: 19556618, 16633321, 18511570, 25433984). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease.
Ambry Genetics	RCV002348143	SCV002647130	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-13	criteria provided, single submitter	clinical testing	The p.H179L variant (also known as c.536A>T), located in coding exon 4 of the TP53 gene, results from an A to T substitution at nucleotide position 536. The histidine at codon 179 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation in yeast based assays (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 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 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). Cells carrying this variant were shown to induce tumor formation when transplanted into mice (Cardinali M et al. Mol Carcinog, 1997 Feb;18:78-88). Two other alterations at the same codon, p.H179Q and p.H179R have been described in individuals with TP53-related disease (Petitjean A et al. IARC TP53 database [version R19, August 2018]. Hum Mutat. 2007 Jun;28(6):622-9;Gonzalez KD et al. J. Med. Genet. 2009 Oct; 46(10):689-93). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Baylor Genetics	RCV003476009	SCV004204285	likely pathogenic	Adrenocortical carcinoma, hereditary	2022-02-07	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000432746	SCV000508390	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439930	SCV000508391	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421837	SCV000508392	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432531	SCV000508393	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444683	SCV000508394	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426806	SCV000508395	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433134	SCV000508396	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443637	SCV000508397	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427517	SCV000508398	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438217	SCV000508399	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420124	SCV000508400	likely pathogenic	Gallbladder carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427330	SCV000508401	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435347	SCV000508402	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418129	SCV000508403	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427941	SCV000508404	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438631	SCV000508405	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418835	SCV000508406	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429543	SCV000508407	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439318	SCV000508408	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only