ClinVar Miner

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

dbSNP: rs1057519989
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000538079 SCV000629861 uncertain significance Li-Fraumeni syndrome 2024-04-15 criteria provided, single submitter clinical testing 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 376599). 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, 29979965). 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.
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.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV002379286 SCV006059708 likely pathogenic Hereditary cancer-predisposing syndrome 2023-11-10 criteria provided, single submitter clinical testing

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