Submissions for variant NM_000546.5(TP53):c.713G>A (p.Cys238Tyr) (rs730882005)

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235220	SCV000211756	likely pathogenic	not provided	2020-11-12	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression activity (Epstein 1998, Kato 2003, Dearth 2007, Monti 2011, Kotler 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 16861262, 26425688, 23297687, 11051239, 21343334, 26619011, 29979965, 30322717, 17606709, 9572492, 16322298, 16818505, 1915267, 19367287, 14673037, 17764544, 28861920, 29177603, 28335073, 30720243, 30840781, 12406399, 11793474, 30352134, 31134617, 31105275, 32622356, 30715630, 30554333, 32152322, 32164171)
Ambry Genetics	RCV000161034	SCV000216065	pathogenic	Hereditary cancer-predisposing syndrome	2017-11-22	criteria provided, single submitter	clinical testing	The p.C238Y pathogenic mutation (also known as c.713G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 713. The cysteine at codon 238 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was identified as de novo in a patient under 20 with osteosarcoma (Spector et al. <span style="color:rgb(0, 0, 0); font-family:arial,helvetica,sans-serif">Cancer Res 2016;76(5 Suppl):Abstract nr A37). <span style="background-color:initial">It has been reported as a somatic mutation 89 times in various tumors and 5 times as a germline mutation by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). This variant is in the DNA binding domain and is one of four amino acid residues required for zinc binding and protein stabilization<span style="background-color:initial"> (Martin et al <span style="background-color:initial">Hum. Mutat. 2002 Feb;19(2):149-64)<span style="background-color:initial">. This variant is reported to have loss of transactivation capacity, and a dominant negative effect <span style="background-color:initial">in yeast-based functional assays <span style="background-color:initial">(IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; <span style="background-color:initial">Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). In addition, this alteration is predicted to be deleterious by in silico analysis. <span style="background-color:initial">Several other alterations at this amino acid position <span style="background-color:initial">(p.C238R<span style="background-color:initial">, <span style="background-color:initial">p.C238G and <span style="background-color:initial">p.C238S)<span style="background-color:initial"> <span style="background-color:initial">have been reported in patients with Li-Fraumeni or Li-Fraumeni-Like syndrome <span style="background-color:initial">(<span style="background-color:initial">Kurtilkova et al Eur J Cancer. 2005 Jul;41(11):1597-603; <span style="background-color:initial">Balma&ntilde;a J et al. <span style="background-color:initial">Med Clin (Barc) 2002 Oct;119(13):497-9<span style="background-color:initial">; <span style="background-color:initial">internal Ambry data). Based on the available evidence, p.C238Y is classified as a pathogenic mutation.
Invitae	RCV000167907	SCV000218555	pathogenic	Li-Fraumeni syndrome	2020-10-19	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with tyrosine at codon 238 of the TP53 protein (p.Cys238Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs730882005, ExAC 0.003%). This variant has been observed in an individual with liposarcoma (Invitae), an individual with osteosarcoma (Invitae), and individuals with Hodgkins disease and breast cancer (PMID: 14673037, 11051239). ClinVar contains an entry for this variant (Variation ID: 182935). Experimental studies have shown that this missense change is a severe deficiency allele, resulting in significantly decreased transactivation activity of TP53, and that it may act in a dominant negative fashion, reducing the transactivation activity of the wild-type allele (PMID: 21343334). However, there is also experimental evidence that this variant has no effect on p53 phosphorylation compared to the wild-type and molecular modeling shows that the structure of the protein is similar (PMID: 16818505). The cysteine residue at codon 238 is involved in coordinating a zinc ion in the DNA-binding domain of the TP53 protein. Furthermore, other amino acid substitutions at this codon have been reported in affected patients, namely Cys238Gly and Cys238Ser. These sequence changes have also been described as severe deficiency alleles (PMID: 21343334). This indicates that the cysteine 238 may be critical for proper protein function. For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc	RCV000161034	SCV000908788	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-04-02	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000442204	SCV000507684	likely pathogenic	Ovarian Serous Cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421991	SCV000507685	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433120	SCV000507686	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442285	SCV000507687	likely pathogenic	Neoplasm of uterine cervix	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426546	SCV000507688	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436794	SCV000507689	likely pathogenic	Uterine Carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444562	SCV000507690	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426733	SCV000507691	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437851	SCV000507692	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420202	SCV000507693	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431283	SCV000507694	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438032	SCV000507695	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417749	SCV000507696	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427976	SCV000507697	likely pathogenic	Adenocarcinoma of stomach	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439129	SCV000507698	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418002	SCV000507699	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429110	SCV000507700	likely pathogenic	Chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne	RCV000785261	SCV000923829	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research
Institute of Medical Sciences, Banaras Hindu University	RCV001374444	SCV001571407	pathogenic	Gallbladder cancer	2020-10-30	no assertion criteria provided	research