ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.824G>T (p.Cys275Phe)

dbSNP: rs863224451
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001861482 SCV002239684 pathogenic Li-Fraumeni syndrome 2024-07-30 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 275 of the TP53 protein (p.Cys275Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 17567834, 18937320). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 376582). 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, 18937320, 29979965, 30224644). This variant disrupts the p.Cys275 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7887414, 12826609, 14584079, 17606709, 21343334; Invitae). 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.
Ambry Genetics RCV004948279 SCV005520039 pathogenic Hereditary cancer-predisposing syndrome 2024-07-08 criteria provided, single submitter clinical testing The p.C275F pathogenic mutation (also known as c.824G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 824. The cysteine at codon 275 is replaced by phenylalanine, an amino acid with highly dissimilar properties. 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 reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). This alteration was identified in an individual diagnosed with breast cancer at 30 (Trkova M et al. Cancer, 2007 Aug;110:694-702). In addition, this alteration was identified in a family that met classic Li-Fraumeni criteria (Capra V et al. Pediatr Blood Cancer, 2009 Feb;52:303-4). This alteration was also identified in an individual diagnosed with gastric cancer at 35 (Masciari S et al. Genet Med, 2011 Jul;13:651-7). 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). Another variant at the same codon, p.C275Y (c.824G>A), has been identified in multiple families that were diagnosed with Li-Fraumeni syndrome (Frebourg T et al. Am. J. Hum. Genet. 1995 Mar; 56(3):608-15; Lynch HT et al. Cancer. 2003 Nov 1;98(9):1947-57). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000785323 SCV000923891 likely pathogenic Ovarian neoplasm 2018-12-01 no assertion criteria provided research

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