Submissions for variant NM_000546.6(TP53):c.526T>C (p.Cys176Arg)

dbSNP: rs967461896

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001023833	SCV001185762	pathogenic	Hereditary cancer-predisposing syndrome	2017-12-21	criteria provided, single submitter	clinical testing	The p.C176R variant (also known as c.526T>C), located in coding exon 4 of the TP53 gene, results from a T to C substitution at nucleotide position 526. The cysteine at codon 176 is replaced by arginine, 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 capacity and a dominant negative effect in yeast based assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Brachmann RK et al. Proc. Natl. Acad. Sci. U.S.A., 1996 Apr;93:4091-5; Dearth LR et al. Carcinogenesis, 2007 Feb;28:289-98). 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; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration is one of four residues necessary to bind the zinc molecule that stabilizes the beta sheet structure of the protein. Any mutation affecting these residues is predicted to prevent or destabilize zinc binding, destabilizing the structure and resulting in loss of function (Martin AC et al. Hum Mutat. 2002 Feb; 19(2):149-64). Another alteration at this same position (TP53 p.C176Y) has been identified in a patient with Li Fraumeni syndrome (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV001044520	SCV001208321	uncertain significance	Li-Fraumeni syndrome	2023-08-17	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 176 of the TP53 protein (p.Cys176Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal and renal tumors (PMID: 26659639). ClinVar contains an entry for this variant (Variation ID: 376573). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000421755	SCV001251936	likely pathogenic	Breast neoplasm	2020-05-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004022206	SCV004932271	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-14	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
Database of Curated Mutations (DoCM)	RCV000436236	SCV000507669	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444713	SCV000507670	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425379	SCV000507671	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436082	SCV000507672	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419681	SCV000507673	likely pathogenic	Papillary renal cell carcinoma type 1	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430429	SCV000507674	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436752	SCV000507675	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419497	SCV000507676	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431070	SCV000507677	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441815	SCV000507678	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423671	SCV000507679	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430876	SCV000507680	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438958	SCV000507681	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421755	SCV000507682	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431573	SCV000507683	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785469	SCV000924041	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research