Submissions for variant NM_000546.6(TP53):c.701A>G (p.Tyr234Cys)

dbSNP: rs587780073

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115732	SCV000149641	pathogenic	not provided	2014-03-10	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.701A>G at the cDNA level and p.Tyr234Cys (Y234C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAC>TGC) in exon 7. This TP53 Tyr234Cys has previously been identified in over 100 tumors as a somatic mutation, most frequently in tumors of the lung, ovaries, brain, breast, and bladder (Petitjean 2007). In addition, this mutation has been observed as a germline mutation in at least one patient with Li Fraumeni syndrome (Pepper 2003). Functional studies have shown loss of transcriptional activation, loss of growth arrest, and loss of induction of apoptosis for this mutation as compared to wild type (Smith 1999, Monti 2007, Monti 2011). Smith et al. (1999) identified that this mutation failed to suppress oncogenic transformation and instead acts as a gain of function mutation, enhancing oncogenic transformation. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Variant Server, suggesting it is not a common benign variant in these populations. This variant is a non-conservative amino acid, altering a position that is well conserved throughout evolution, and is located in the DNA domain which interacts with HIPK1, ZNF385A, FOXO42, and AXIN1 (UniProt). Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. We therefore consider this mutation to be pathogenic. This variant has been seen apparently mosaic. The variant is found in ENDOM-HEREDIC panel(s).
Invitae	RCV000200601	SCV000253701	pathogenic	Li-Fraumeni syndrome	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 234 of the TP53 protein (p.Tyr234Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of TP53-related conditions (PMID: 12695689, 26556299, 28724667; Invitae). ClinVar contains an entry for this variant (Variation ID: 127820). 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: 10229196, 16861262, 17606709, 21343334). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000492245	SCV000581157	pathogenic	Hereditary cancer-predisposing syndrome	2020-07-14	criteria provided, single submitter	clinical testing	The p.Y234C pathogenic mutation (also known as c.701A>G), located in coding exon 6 of the TP53 gene, results from an A to G substitution at nucleotide position 701. The tyrosine at codon 234 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in an individual with a personal history of B-CLL and leiomyosarcoma, and a family history of sarcoma, breast cancer, and leukemia (Pepper C et al. Cell Cycle. 2003 Jan-Feb;2(1):53-8). This alteration was also detected in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing (Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119). This alteration has been shown to be deficient in transactivation and exhibits dominant negative properties in studies conducted in both yeast and mammalian cells (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Mol Cancer Res. 2011 Mar;9(3):271-9; Dearth LR et al. Carcinogenesis. 2007 Feb;28:289-98). 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). In addition, two other alterations at this position (p.Y234D, p.Y234H) have been identified in patients meeting criteria for Li-Fraumeni syndrome (Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a significant 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. 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.
Genetic Services Laboratory, University of Chicago	RCV000200601	SCV000597518	likely pathogenic	Li-Fraumeni syndrome	2016-10-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000115732	SCV002020263	likely pathogenic	not provided	2019-05-11	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV001808343	SCV002059230	pathogenic	Li-Fraumeni syndrome 1	2020-06-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000492245	SCV002582370	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001808343	SCV002583030	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001808343	SCV004933056	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-16	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 10229196, 20505364].
Database of Curated Mutations (DoCM)	RCV000433924	SCV000510285	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445147	SCV000510286	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422171	SCV000510287	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432406	SCV000510288	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444325	SCV000510289	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425854	SCV000510290	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435258	SCV000510291	likely pathogenic	Adrenal cortex carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444475	SCV000510292	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425220	SCV000510293	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435287	SCV000510294	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420460	SCV000510295	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430670	SCV000510296	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438314	SCV000510297	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420651	SCV000510298	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785536	SCV000924108	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research