ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.824G>A (p.Cys275Tyr) (rs863224451)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197359 SCV000253702 pathogenic Li-Fraumeni syndrome 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 275 of the TP53 protein (p.Cys275Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals and families affected with Li-Fraumeni syndrome (PMID: 7887414, 14584079, 17606709, Invitae), and an individual affected with chronic lymphocytic leukemia (PMID: 19850740). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 215997). Functional analysis of this variant in transactivation assays using yeast model system shows this variant is non-functional (PMID: 12826609, 21343334). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000235315 SCV000293284 pathogenic not provided 2015-10-26 criteria provided, single submitter clinical testing This pathogenic variant is denoted TP53 c.824G>A at the cDNA level, p.Cys275Tyr (C275Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant has been reported in at least two families with multiple sarcomas meeting Chompret criteria (Frebourg 1995, Lynch 2003). Multiple yeast- and tumor-based functional assays have found that TP53 Cys275Tyr eliminates or greatly reduces transcriptional activity of several p53-responsive elements (Tada 1997, Flaman 1998, Marutani 1999, Waddell 2001, Deissler 2004). This variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003) and is classified as a severe deficiency allele by Monti et al. (2011). TP53 Cys275Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Cys275Tyr occurs at a position that is conserved across species and is located in the DNA binding domain and region of interaction with multiple proteins (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000568594 SCV000664383 pathogenic Hereditary cancer-predisposing syndrome 2020-09-11 criteria provided, single submitter clinical testing The p.C275Y pathogenic mutation (also known as c.824G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 824. The cysteine at codon 275 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation was identified as a germline alteration in three individuals from a family with Li-Fraumeni syndrome (LFS), where the proband had a rhabadomyosarcoma at 2 years of age, the father with sarcoma at 34y, and a paternal uncle with sarcoma at 22y and 27y (Frebourg T et al. Am. J. Hum. Genet. 1995 Mar; 56(3):608-15). This mutation has also been identified as a germline alteration in a separate LFS family, where 16 family members had 18 sarcomas of various types, as well as breast cancer and leukemia (Lynch HT et al. Cancer. 2003 Nov 1;98(9):1947-57). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and dominant negative effect in yeast-based assays (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P, Mol. Cancer Res. 2011 Mar; 9(3):271-9). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and is deficient at growth suppression in vitro (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, residue 275 of the p53 protein has been shown by crystal structure to be involved in DNA contact (Martin AC et al. Hum. Mutat. 2002 Feb; 19(2):149-64). 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.
Color RCV000568594 SCV001359331 likely pathogenic Hereditary cancer-predisposing syndrome 2020-04-10 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000439245 SCV000507824 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422025 SCV000507825 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429197 SCV000507826 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439892 SCV000507827 likely pathogenic Chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422663 SCV000507828 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433358 SCV000507829 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443293 SCV000507830 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423497 SCV000507831 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434190 SCV000507832 likely pathogenic Renal cell carcinoma, papillary, 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442329 SCV000507833 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427629 SCV000507834 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438333 SCV000507835 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442357 SCV000507836 likely pathogenic Adrenocortical carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424784 SCV000507837 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435410 SCV000507838 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418175 SCV000507839 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785533 SCV000924105 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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