Submissions for variant NM_000546.6(TP53):c.713G>A (p.Cys238Tyr)

gnomAD frequency: 0.00001  dbSNP: rs730882005

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235220	SCV000211756	likely pathogenic	not provided	2021-11-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression activity (Epstein 1998, Kato 2003, Dearth 2007, Monti 2011, Kotler 2018); Not observed at a significant frequency 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: 16861262, 26425688, 23297687, 11051239, 21343334, 26619011, 29979965, 30322717, 17606709, 9572492, 16322298, 16818505, 1915267, 19367287, 14673037, 17764544, 28861920, 29177603, 28335073, 30720243, 30840781, 12406399, 11793474, 30352134, 31134617, 30715630, 30554333, 32152322, 32164171, 12826609, 34332791, 34548910, 32547059, 33309985, 31105275, 32622356, 34234554, 32971811)
Ambry Genetics	RCV000161034	SCV000216065	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-08	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. Cancer Res 2016;76(5 Suppl):Abstract nr A37). This alteration has been reported in a 15 year-old individual with a personal history of pleomorphic myxoid liposarcoma and the patient's mother, who had a personal history of pre-menopausal breast cancer; there was also a strong family history of malignancy (Sinclair TJ et al. Pediatr Surg Int, 2017 May;33:631-635). This variant was also identified in a cohort of 4439 women with ovarian cancer undergoing multigene panel testing at one laboratory (Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488). This variant is in the DNA binding domain and is one of four amino acid residues required for zinc binding and protein stabilization (Martin et al Hum. Mutat. 2002 Feb;19(2):149-64). This variant is reported to have loss of transactivation capacity, and a dominant negative effect in yeast-based functional assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):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 alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). In addition, this alteration is predicted to be deleterious by in silico analysis. Several other alterations at this amino acid position (p.C238R, p.C238G and p.C238S) have been reported in patients with Li-Fraumeni or Li-Fraumeni-Like syndrome (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; internal Ambry data). Based on the available evidence, p.C238Y is classified as a pathogenic mutation.
Invitae	RCV000167907	SCV000218555	pathogenic	Li-Fraumeni syndrome	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 238 of the TP53 protein (p.Cys238Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with breast cancer, Hodgkins disease, liposarcoma, and/or osteosarcoma (PMID: 11051239, 14673037; Invitae). ClinVar contains an entry for this variant (Variation ID: 182935). 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, 21343334, 29979965, 30224644). 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: 12506399, 15925506, 21343334). 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.
Color Diagnostics, LLC DBA Color Health	RCV000161034	SCV000908788	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 238 of the TP53 protein. The cysteine residue at codon 238 is one of the cysteine ligands required for the tetrahedrally coordinated zinc atom important for the structure and DNA binding activity of the TP53 DNA binding domain (PMID: 8276238, 8023157, 11793474). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Multiple functional studies have shown that the mutant protein is non-functional in growth suppression and transactivation assays (PMID: 12826609, 17606709, 21343334, 30224644) and has a dominant-negative effect on growth suppression (PMID: 30224644). However, one study had previously reported contradictory findings in limited transactivation and DNA damage response assays (PMID: 16818505). This variant has been reported in individuals affected with breast cancer (PMID: 11051239, 31105275, 33471991), sarcoma (PMID: 31105275), osteosarcoma (DOI: 10.1158/1538-7445.PEDCA15-A37), pleomorphic myxoid liposarcoma (PMID: 28160093), ovarian cancer (PMID: 30322717), Hodgkin's disease (PMID: 14673037), and two individuals affected with malignant peripheral nerve sheath tumor, one of whom also had childhood onset non-Hodgkin's lymphoma (PMID: 16818505). This variant has been identified in 2/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Multiple variants affecting the same position, p.Cys238Trp, p.Cys238Phe, p.Cys238Arg and p.Cys238Ser, are considered to be disease-causing (ClinVar variation ID: 161515, 376574, 376576, 485039). Based on the available evidence, this variant is classified as Pathogenic.
Genome-Nilou Lab	RCV000161034	SCV002582368	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288693	SCV002583029	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462109	SCV004206249	pathogenic	Adrenocortical carcinoma, hereditary	2023-08-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288693	SCV004931630	pathogenic	Li-Fraumeni syndrome 1	2024-02-16	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965, 7478555, 21343334, 7791795]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 28160093].
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	Gastric adenocarcinoma	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	B-cell chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785261	SCV000923829	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research
Institute of Medical Sciences, Banaras Hindu University	RCV001374444	SCV001571407	pathogenic	Gallbladder cancer	2020-10-30	no assertion criteria provided	research