Submissions for variant NM_000546.6(TP53):c.730G>T (p.Gly244Cys)

dbSNP: rs1057519989

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000538079	SCV000629861	uncertain significance	Li-Fraumeni syndrome	2023-06-29	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965). 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. ClinVar contains an entry for this variant (Variation ID: 376599). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 244 of the TP53 protein (p.Gly244Cys).
Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo	RCV001270273	SCV001450490	pathogenic	Familial cancer of breast		criteria provided, single submitter	case-control
GeneDx	RCV001567979	SCV001791762	pathogenic	not provided	2019-12-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression ability (Kato 2003, Kotler 2018); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31711486, 30123427, 31186738, 31588418, 29979965, 10226610, 20557307, 22931248, 22551440, 15580553, 11307149, 15902285, 14722922, 19558493, 31168460)
Ambry Genetics	RCV002379286	SCV002674361	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-14	criteria provided, single submitter	clinical testing	The p.G244C pathogenic mutation (also known as c.730G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at nucleotide position 730. The glycine at codon 244 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8). Another alteration at this position [p.G244S (c.730G>A)] has been reported in individuals with features of Li-Fraumeni syndrome (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9; Arcand SL et al. BMC Med. Genet. 2015 Apr;16:24; Hu H et al. Sci Rep. 2016 Jan;6:20221). The p.G244C 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). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, p.G244C is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Database of Curated Mutations (DoCM)	RCV000437805	SCV000508147	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443459	SCV000508148	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427774	SCV000508149	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436692	SCV000508150	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419449	SCV000508151	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430162	SCV000508152	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437360	SCV000508153	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418385	SCV000508154	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429067	SCV000508155	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439724	SCV000508156	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422508	SCV000508157	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427875	SCV000508158	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438569	SCV000508159	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only