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

dbSNP: rs1057519981

Total submissions: 21

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.
Invitae	RCV000812726	SCV000953049	pathogenic	Li-Fraumeni syndrome	2019-04-03	criteria provided, single submitter	clinical testing	An experimental study in yeast has shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). This variant has been observed to be de novo in an individual affected with choroid plexus carcinoma (Invitae). ClinVar contains an entry for this variant (Variation ID: 376576). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 238 of the TP53 protein (p.Cys238Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant disrupts the p.C238 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID:  12406399, 14673037, 15925506), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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
Database of Curated Mutations (DoCM)	RCV000437018	SCV000507735	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419348	SCV000507736	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430482	SCV000507737	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437199	SCV000507738	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420409	SCV000507739	likely pathogenic	Neoplasm of uterine cervix	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430655	SCV000507740	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441834	SCV000507741	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424052	SCV000507742	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428210	SCV000507743	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438447	SCV000507744	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421679	SCV000507745	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431946	SCV000507746	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441879	SCV000507747	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421933	SCV000507748	likely pathogenic	B-cell chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433046	SCV000507749	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442237	SCV000507750	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426193	SCV000507751	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only