ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.472C>T (p.Arg158Cys) (rs587780068)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115723 SCV000185723 likely pathogenic Hereditary cancer-predisposing syndrome 2017-01-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Well-characterized mutation at same position,Structural Evidence
Color RCV000115723 SCV000908793 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-23 criteria provided, single submitter clinical testing
GeneDx RCV000508084 SCV000149632 uncertain significance not provided 2015-06-08 criteria provided, single submitter clinical testing This variant is denoted TP53 c.472C>T at the cDNA level, p.Arg158Cys (R158C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant was observed in the germline of a male patient with a history of adrenocortical carcinoma and teratocarcinoma of the testis where loss of heterozygosity of the wild-type allele and negative staining of the p53 protein via immunohistochemistry were observed in the adrenal tumor tissue (Herrmann 2011). In vitro yeast-based assays have demonstrated this variant to be temperature sensitive and to inhibit transactivation (Shiraishi 2004, Monti 2003). TP53 Arg158Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Arg158Cys occurs at a position that is not conserved, with Cysteine being the naturally occurring amino acid at this position in one mammal, and is located in the DNA binding domain and region of interaction with HIPK1, ZNF385A, FBXO42 and AXIN1 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether TP53 Arg158Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000533951 SCV000629824 uncertain significance Li-Fraumeni syndrome 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 158 of the TP53 protein (p.Arg158Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587780068, ExAC 0.003%). This variant has been reported in an individual affected with adrenocortical carcinoma and testicular cancer (PMID: 22170717) as well as in an individual affected with breast cancer (PMID: 28724667). ClinVar contains an entry for this variant (Variation ID: 127812). Experimental studies in yeast has shown that this variant partially impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609, 12917626, 14559903) Different missense substitutions at this codon (p.Arg158His and p.Arg158Leu) have been determined to be pathogenic (PMID: 10486318, 23894400, 20455025, 20522432, 25584008, 21343334, 10229196, 16861262, 12725534). This suggests that the arginine residue is critical for TP53 protein function and that other missense substitutions at this position may also be pathogenic. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508084 SCV000602273 likely pathogenic not provided 2016-09-28 criteria provided, single submitter clinical testing

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