Submissions for variant NM_000546.5(TP53):c.700T>G (p.Tyr234Asp) (rs864622237)

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204217	SCV000259812	uncertain significance	Li-Fraumeni syndrome	2015-08-07	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine with aspartic acid at codon 234 of the TP53 protein (p.Tyr234Asp). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and aspartic acid. This variant is not present in population databases and has been reported in the literature. This variant was reported in an individual affected with chronic lymphocytic leukemia (PMID: 21232794). It has also been reported in the tumor of a patient with colorectal cancer (PMID: 22982087). Experimental studies in vitro have shown that this missense change may lead to defective transactivation (PMID: 21232794). Other missense mutations, p.Tyr234Cys and p.Tyr234His, have been reported at the same codon in individuals affected with Li-Fraumeni syndrome as well as other isolated cancers (PMID: 12695689, 17606709, 23894400). Experimental studies of these missense mutations suggest that this amino acid may be essential for protein function (PMID: 9290701, 21232794, 21343334). In summary, clinical and experimental evidence suggests that other missense mutations at this position may lead to disrupted protein function. However, evidence directly related this p.Tyr234Asp variant is limited. For these reasons, this change has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000492197	SCV000581114	likely pathogenic	Hereditary cancer-predisposing syndrome	2016-03-18	criteria provided, single submitter	clinical testing	The p.Y234D variant (also known as c.700T>G), located in coding exon 6 of the TP53 gene, results from a T to G substitution at nucleotide position 700. The tyrosine at codon 234 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This variantwas detected in an individual meeting clinical criteria forclassicLi-Fraumenisyndrome(Ambryinternal data).This variant is in the DNA binding domain of theTP53protein and is reported to have loss oftransactivationcapacity and predicted toaffectseveral p53isoforms. (IARCTP53database; Kato S et al.ProcNatlAcadSci USA. 2003 Jul 8;100(14):8424-9).This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position.To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 250000alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. However, based on internal structural analysis, this variant may result in a decrease in structural stability (Cho Y et al.Science1994 Jul; 265(5170):346-55).Additionally, adifferent alterationat the samecodon,p.Y234H, hasbeenreportedin an individual with breast cancer at age 33 and aleiomyosarcomaat age 48,with loss ofheterozygositypresentin the tumor (Mitchell G et al.PLoSONE2013 ; 8(7):e69026).Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Database of Curated Mutations (DoCM)	RCV000418073	SCV000510341	likely pathogenic	Adenocarcinoma of prostate	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430896	SCV000510342	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441597	SCV000510343	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424345	SCV000510344	likely pathogenic	Adenocarcinoma of stomach	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433328	SCV000510345	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440475	SCV000510346	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423238	SCV000510347	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433956	SCV000510348	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445176	SCV000510349	likely pathogenic	Ovarian Serous Cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425587	SCV000510350	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432845	SCV000510351	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445265	SCV000510352	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424462	SCV000510353	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435222	SCV000510354	likely pathogenic	Adrenocortical carcinoma	2016-05-31	no assertion criteria provided	literature only