Submissions for variant NM_000546.6(TP53):c.700T>C (p.Tyr234His)

dbSNP: rs864622237

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492782	SCV000581136	pathogenic	Hereditary cancer-predisposing syndrome	2019-05-29	criteria provided, single submitter	clinical testing	The p.Y234H pathogenic mutation (also known as c.700T>C), located in coding exon 6 of the TP53 gene, results from a T to C substitution at nucleotide position 700. The tyrosine at codon 234 is replaced by histidine, an amino acid with some similar properties. This alteration was confirmed as a de novo alteration in a 10 month old patient with a rhabdomyosarcoma (Ambry internal data), and was reported in an individual with breast cancer at 33 and a leiomyosarcoma at 48 with loss of heterozygosity in the tumor (Mitchell G et al. PLoS ONE 2013 ; 8(7):e69026). This variant is located in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and deficient apoptosis induction (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul; 100(14):8424-9; Smith PD et al. Oncogene 1999 Apr; 18(15):2451-9). 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). Based on internal structural analysis, this variant may result in a decrease in structural stability (Cho Y et al. Science 1994 Jul; 265(5170):346-55). This amino acid position is well conserved in available vertebrate species. Based on the available evidence, p.Y234H is classified as a pathogenic mutation.
Invitae	RCV000530551	SCV000629855	pathogenic	Li-Fraumeni syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 234 of the TP53 protein (p.Tyr234His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li Fraumeni syndrome (PMID: 23894400; Invitae). ClinVar contains an entry for this variant (Variation ID: 376691). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 8080050, 9525742, 10229196, 10871862, 11429705, 11896595, 12826609, 22710932). This variant disrupts the p.Tyr234 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12695689, 26556299, 28724667; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000492782	SCV002582473	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289544	SCV002583134	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002289544	SCV004932056	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-15	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965, 10229196, 10871862]. This variant is expected to disrupt protein structure [Myriad internal data].
Database of Curated Mutations (DoCM)	RCV000427499	SCV000510313	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436907	SCV000510314	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419222	SCV000510315	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426894	SCV000510316	likely pathogenic	Adrenal cortex carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437128	SCV000510317	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418604	SCV000510318	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428839	SCV000510319	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439967	SCV000510320	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418790	SCV000510321	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428164	SCV000510322	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438411	SCV000510323	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421640	SCV000510324	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431867	SCV000510325	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441352	SCV000510326	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785304	SCV000923872	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research