Submissions for variant NM_000546.6(TP53):c.528C>G (p.Cys176Trp)

dbSNP: rs1057519980

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000530055	SCV000629832	likely pathogenic	Li-Fraumeni syndrome	2020-02-04	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys176 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27622479, 12826609, 9572492). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect TP53 protein function (PMID: 12826609, 19850740). This variant has not been reported in the literature in individuals with TP53-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tryptophan at codon 176 of the TP53 protein (p.Cys176Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan.
Ambry Genetics	RCV000567103	SCV000664440	uncertain significance	Hereditary cancer-predisposing syndrome	2017-04-17	criteria provided, single submitter	clinical testing	The p.C176W variant (also known as c.528C>G), located in coding exon 4 of the TP53 gene, results from a C to G substitution at nucleotide position 528. The cysteine at codon 176 is replaced by tryptophan, an amino acid with highly dissimilar properties. This alteration was shown to have a loss of transactivation capacity in yeast-based functional studies (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003401413	SCV004110701	uncertain significance	TP53-related disorder	2023-09-24	criteria provided, single submitter	clinical testing	The TP53 c.528C>G variant is predicted to result in the amino acid substitution p.Cys176Trp. To our knowledge, this variant has not been reported in association with disorders as a germline variant in the literature. Functional studies showed that this variant results in ~11.31% transcriptional activity compared to wildtype TP53 protein (Kato et al. 2003. PubMed ID: 12826609; see data in http://mutantp53.broadinstitute.org/?query=p.C176W) and could alter downstream target gene expressions (Figure 4, Malcikova et al. 2009. PubMed ID: 19850740). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Different nucleotide substitutions affecting the same amino acid (p.Cys176Ser, p.Cys176Arg, p.Cys176Tyr, and p.Cys176Phe) have been reported to be associated with Li-Fraumeni syndrome-associated cancers (Human Gene Mutation Database). The c.528C>G (p.Cys176Trp) variant has conflicting interpretations of pathogenicity in ClinVar ranging from uncertain to likely pathogenic (http://www.ncbi.nlm.nih.gov/clinvar/variation/376572). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Myriad Genetics, Inc.	RCV004022205	SCV004933804	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)	RCV000429475	SCV000507654	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439276	SCV000507655	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418563	SCV000507656	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430137	SCV000507657	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440822	SCV000507658	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422732	SCV000507659	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429952	SCV000507660	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441518	SCV000507661	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424249	SCV000507662	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434070	SCV000507663	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442369	SCV000507664	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421434	SCV000507665	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432087	SCV000507666	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445065	SCV000507667	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424653	SCV000507668	likely pathogenic	Papillary renal cell carcinoma type 1	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785243	SCV000923811	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research
BRCAlab, Lund University	RCV000567103	SCV002589028	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-08-26	no assertion criteria provided	clinical testing