Submissions for variant NM_000546.6(TP53):c.487T>G (p.Tyr163Asp)

dbSNP: rs786203436

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166739	SCV000217550	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-09-20	criteria provided, single submitter	clinical testing	The p.Y163D variant (also known as c.487T>G), located in coding exon 4 of the TP53 gene, results from a T to G substitution at nucleotide position 487. The tyrosine at codon 163 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This alteration is located in the DNA binding domain and has been shown to be non-functional in yeast-based functional studies (Kato, S et al. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):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). Another alteration at this same location, p.Y163C, has been identified in two different Li-Fraumeni families. The proband in each case had multiple primary childhood cancers; all in the LFS spectrum of cancers. (Villani et. al., Lancet Oncology. 2011; 12: 559; McIntyre JF, J. Clin. Oncol. 1994 May; 12(5):925-30). Additionally, structural analysis had indicated that the Y163C alteration results in altered fold stability and would influence both DNA binding and tetramerization (internal analysis). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well 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	RCV001850353	SCV002288206	uncertain significance	Li-Fraumeni syndrome	2021-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine with aspartic acid at codon 163 of the TP53 protein (p.Tyr163Asp). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and aspartic acid. 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: 187052). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (ExAC no frequency).
Database of Curated Mutations (DoCM)	RCV000433509	SCV000510099	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444147	SCV000510100	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426124	SCV000510101	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432709	SCV000510102	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443587	SCV000510103	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425235	SCV000510104	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435516	SCV000510105	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417885	SCV000510106	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424608	SCV000510107	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434903	SCV000510108	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420721	SCV000510109	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430982	SCV000510110	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441262	SCV000510111	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420162	SCV000510112	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only