Submissions for variant NM_000546.6(TP53):c.713G>C (p.Cys238Ser)

dbSNP: rs730882005

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001067780	SCV001232859	pathogenic	Li-Fraumeni syndrome	2022-10-29	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 376575). This missense change has been observed in individual(s) with breast and/or ovarian cancer and/or clinical features of Li-Fraumeni Syndrome (PMID: 29470806, 34308366). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 238 of the TP53 protein (p.Cys238Ser). For these reasons, this variant has been classified as Pathogenic. 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.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV001523834	SCV001478192	likely pathogenic	Li-Fraumeni syndrome 1	2020-12-15	criteria provided, single submitter	research
GeneDx	RCV001551247	SCV001771714	pathogenic	not provided	2019-06-07	criteria provided, single submitter	clinical testing	Not observed 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: 30840781, 29843463, 28160562, 29470806, 19681600, 29979965, 21343334, 20126990, 21197471, 7732013, 25294809, 25105660, 11166732, 14559903, 28303898, 29580149)
Genome-Nilou Lab	RCV002289520	SCV002582367	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001523834	SCV002583028	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002289520	SCV002662724	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-14	criteria provided, single submitter	clinical testing	The p.C238S pathogenic mutation (also known as c.713G>C), located in coding exon 6 of the TP53 gene, results from a G to C substitution at nucleotide position 713. The cysteine at codon 238 is replaced by serine, an amino acid with dissimilar properties. This variant was detected in a classic LFS family, where the proband had leiomyosarcoma, his brother had colon cancer at 28, and his two nieces had brain cancer at ages 13 and 8 (Balmaña J, Med Clin (Barc) 2002 Oct; 119(13):497-9). This variant was observed in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer in a patient with a personal history of breast cancer diagnosed at age 30 (Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196). This variant is reported to have non-functional transactivation and a dominant negative effect in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant is in the DNA binding domain of the TP53 protein and is one of four cysteine 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 decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV001523834	SCV004931248	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: 7791795, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
Database of Curated Mutations (DoCM)	RCV000439773	SCV000507718	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419485	SCV000507719	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429749	SCV000507720	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440842	SCV000507721	likely pathogenic	Neoplasm of uterine cervix	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423226	SCV000507722	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434344	SCV000507723	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441115	SCV000507724	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424302	SCV000507725	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434584	SCV000507726	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442617	SCV000507727	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424531	SCV000507728	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432222	SCV000507729	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442527	SCV000507730	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425465	SCV000507731	likely pathogenic	B-cell chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435732	SCV000507732	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418923	SCV000507733	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425867	SCV000507734	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only