ClinVar Miner

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

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235220 SCV000211756 likely pathogenic not provided 2018-05-21 criteria provided, single submitter clinical testing This variant is denoted TP53 c.713G>A at the cDNA level, p.Cys238Tyr (C238Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant has been observed in either the homozygous or hemizygous state in blood cells from an individual with a history of Hodgkin's disease and other personal/family history not consistent with Li-Fraumeni syndrome (Nichols 2003). Although reported as a germline finding, testing of a second tissue was not performed, leaving open the possibility that this variant was present due to a somatic event in this individual's blood cells. Functional studies have demonstrated TP53 Cys238Tyr to impact transactivation (Epstein 1998, Dearth 2007, Monti 2011), consistent with it being reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Cys238Tyr was not observed in large population cohorts (Lek 2016). This variant is located within the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider TP53 Cys238Tyr to be a likely pathogenic variant.
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 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

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