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

gnomAD frequency: 0.00001  dbSNP: rs863224451

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197359	SCV000253702	pathogenic	Li-Fraumeni syndrome	2025-01-22	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; internal data). 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). Invitae Evidence Modeling incorporating data from in vitro 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	2024-04-22	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
All of Us Research Program, National Institutes of Health	RCV000197359	SCV004823763	pathogenic	Li-Fraumeni syndrome	2023-05-30	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.
Myriad Genetics, Inc.	RCV002288809	SCV004932963	pathogenic	Li-Fraumeni syndrome 1	2024-02-20	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7887414, 14584079].
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785533	SCV000924105	likely pathogenic	Ovarian neoplasm	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