Submissions for variant NM_000546.6(TP53):c.824G>A (p.Cys275Tyr)

gnomAD frequency: 0.00001  dbSNP: rs863224451

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000197359	SCV000253702	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 275 of the TP53 protein (p.Cys275Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with chronic lymphocytic leukemia and Li-Fraumeni syndrome (PMID: 7887414, 14584079, 17606709, 19850740; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 215997). 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). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000235315	SCV000293284	pathogenic	not provided	2021-04-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation with a dominant-negative effect, loss of growth suppression and apoptotic activities (Flaman 1998, Waddell 2001, Kato 2003, Bergamaschi 2003, Monti 2011, Kotler 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12726864, 30720243, 9546439, 29979965, 31105275, 17606709, 21343334, 9115587, 8458321, 11593407, 10519380, 12826609, 29489754, 30840781, 14584079, 7887414, 15138567, 15541116, 33818021)
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 Diagnostics, LLC DBA Color Health	RCV000568594	SCV001359331	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 275 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental studies have shown that this variant disrupted function in yeast transactivation assays (PMID: 12826609), human cell proliferation assays (PMID: 29979965), and human cell growth suppression assays (PMID: 30224644). This variant has been reported in individuals affected with Li-fraumeni syndrome (PMID: 7887414, 14584079; ClinVar SCV000253702.9) and early-onset breast cancer meeting Chompret criteria (PMID: 33818021, 34793666, 35127508). In at least two families, this variant co-segregated with Li-fraumeni syndrome (PMID: 7887414, 14584079). This variant has also been reported in chronic lymphocytic leukemia (PMID: 19850740, 21232794, 22983585), and other cancers (PMID: 11051239, 26425688). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.824G>T (p.Cys275Phe), is considered to be disease-causing (ClinVar Variation ID: 376582), suggesting that cysteine at this position is important for the protein function. Based on the available evidence, this variant is classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000235315	SCV002498238	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	TP53: PP1:Strong, PM1, PM2, PM5, PS3:Moderate, PS4:Moderate
Genome-Nilou Lab	RCV000568594	SCV002582351	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288809	SCV002583012	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468892	SCV004206271	pathogenic	Adrenocortical carcinoma, hereditary	2023-06-08	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	B-cell 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	Papillary renal cell carcinoma type 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	Adrenal cortex 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, University Hospital Cologne	RCV000785533	SCV000924105	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001610519	SCV001832549	pathogenic	Breast carcinoma	2021-09-04	no assertion criteria provided	clinical testing
Ayesha Lab, University of the Punjab	RCV003320135	SCV004024445	likely pathogenic	Acute myeloid leukemia		no assertion criteria provided	clinical testing