Submissions for variant NM_000546.6(TP53):c.487T>C (p.Tyr163His)

dbSNP: rs786203436

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001023195	SCV001185033	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-23	criteria provided, single submitter	clinical testing	The p.Y163H variant (also known as c.487T>C), located in coding exon 4 of the TP53 gene, results from a T to C substitution at nucleotide position 487. The tyrosine at codon 163 is replaced by histidine, an amino acid with similar 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 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 in at least one individual with a personal and/or family history that is consistent with TP53-related disease (external communication) and has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). 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). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV001071488	SCV001236795	uncertain significance	Li-Fraumeni syndrome	2019-11-18	criteria provided, single submitter	clinical testing	This variant has been reported to affect TP53 protein function (PMID: 12826609). This variant has not been reported in the literature in individuals with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 376680). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with histidine at codon 163 of the TP53 protein (p.Tyr163His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant disrupts the p.Tyr163 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18685109, 19556618, 25584008, 11051239, 25757876). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Genome-Nilou Lab	RCV001023195	SCV002582072	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289543	SCV002582635	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003476012	SCV004204251	likely pathogenic	Adrenocortical carcinoma, hereditary	2023-04-13	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000436639	SCV000510085	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418859	SCV000510086	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425645	SCV000510087	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435900	SCV000510088	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418221	SCV000510089	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428451	SCV000510090	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438678	SCV000510091	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417511	SCV000510092	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431265	SCV000510093	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441609	SCV000510094	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423893	SCV000510095	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434193	SCV000510096	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440924	SCV000510097	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423239	SCV000510098	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only