Submissions for variant NM_000546.6(TP53):c.712T>C (p.Cys238Arg)

dbSNP: rs1057519981

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492666	SCV000581087	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	The p.C238R pathogenic mutation (also known as c.712T>C), located in coding exon 6 of the TP53 gene, results from a T to C substitution at nucleotide position 712. The cysteine at codon 238 is replaced by arginine, an amino acid with highly dissimilar properties. Although this specific alteration has not been reported in the literature, several other alterations at this amino acid position (p.C238S, p.C238G and p.C238Y) have been reported in patients with Li-Fraumeni or Li-Fraumeni-Like syndrome and classified as severe deficiency alleles based on functional studies (Kurtilkova et al Eur J Cancer. 2005 Jul;41(11):1597-603; Balmaña J et al. Med Clin (Barc) 2002 Oct;119(13):497-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9); internal Ambry data). This variant is reported to have loss of transactivation capacity in yeast based functional assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). This alteration is located in the DNA binding domain of the TP53 protein and is one of four residues involved in binding a zinc atom necessary for the protein to adopt the correct conformation (Martin et al Hum. Mutat. 2002 Feb;19(2):149-64). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis.This amino acid position is highly conserved in available vertebrate species. Based on the available evidence, p.C238R is classified as a pathogenic mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812726	SCV000953049	pathogenic	Li-Fraumeni syndrome	2024-05-09	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 238 of the TP53 protein (p.Cys238Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with choroid plexus carcinoma (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376576). 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: 12826609). This variant disrupts the p.Cys238 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12406399, 14673037, 15925506). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000492666	SCV002582472	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289521	SCV002583133	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002289521	SCV004932584	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-16	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 7478555, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].