Submissions for variant NM_000546.6(TP53):c.527G>A (p.Cys176Tyr)

dbSNP: rs786202962

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166045	SCV000216806	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-23	criteria provided, single submitter	clinical testing	The p.C176Y pathogenic mutation (also known as c.527G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 527. The cysteine at codon 176 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration is located in the highly conserved domain IV of the DNA binding domain, and is one of four residues necessary to bind the zinc molecule that stabilizes the beta sheet structure of the protein (Martin AC et al. Hum Mutat. 2002 Feb;19(2):149-64). Multiple yeast-based functional studies have demonstrated a loss of transactivation capability for this variant (Epstein CB et al. Oncogene 1998 Apr;16(16):2115-22; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Hassan NM et al. Cancer Lett. 2008 Oct; 270(1):108-19). 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 has been detected in at least one individual with classic Li-Fraumeni syndrome (LFS) tested by our laboratory (Ambry internal data), and was reported as a de novo alteration in an individual diagnosed with adrenocortical carcinoma at age 5 (Renaux-Petel M et al. J. Med. Genet. 2018 03;55(3):173-180). 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.
GeneDx	RCV000255616	SCV000322087	pathogenic	not provided	2021-05-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation and impaired cell growth suppression ability (Epstein 1998, Kato 2003, Joerger 2010, Eldar 2013, Kotler 2018); Not observed in large population cohorts (Lek 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: 23863845, 15280671, 20516128, 23967324, 25232094, 18555592, 12726864, 9572492, 12509970, 10519380, 26585234, 26552420, 29979965, 29070607, 30720243, 31105275, 30840781, 32885271)
Invitae	RCV000461158	SCV000545328	pathogenic	Li-Fraumeni syndrome	2024-01-03	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 176 of the TP53 protein (p.Cys176Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with adrenocortical carcinoma (PMID: 29070607). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 186451). 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: 9572492, 12826609, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000166045	SCV002582492	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288754	SCV002583152	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Liquid Biopsy and Cancer Interception Group, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research	RCV003128588	SCV003806309	pathogenic	Squamous cell carcinoma	2022-06-06	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV003407616	SCV004111842	pathogenic	TP53-related disorder	2023-02-20	criteria provided, single submitter	clinical testing	The TP53 c.527G>A variant is predicted to result in the amino acid substitution p.Cys176Tyr. This variant was reported in a patient with adrenocortical carcinoma (Patient F279 in Renaux-Petel et al 2018. PubMed ID: 29070607) and in a patient with ovarian and breast cancer (Supplemental Table, Lerner-Ellis. 2020. PubMed ID: 32885271). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This has been interpreted as likely pathogenic or pathogenic by several submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/186451/). Of note, other variants impacting the same amino acid residue (p.Cys176Ser, p.Cys176Arg, p.Cys176Phe), have also been reported in patients with TP53-related disorders (Table S10 in Maxwell et al. 2016. PubMed ID: 27153395; Whitworth et al. 2016. PubMed ID: 26659639; Human Gene Mutation Database). Based on this evidence, we interpret the c.527G>A (p.Cys176Tyr) variant as pathogenic.
Baylor Genetics	RCV003474872	SCV004204270	pathogenic	Adrenocortical carcinoma, hereditary	2022-10-13	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000435778	SCV000507609	likely pathogenic	Papillary renal cell carcinoma type 1	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418577	SCV000507610	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430147	SCV000507611	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437356	SCV000507612	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419236	SCV000507613	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429854	SCV000507614	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441417	SCV000507615	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424233	SCV000507616	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430568	SCV000507617	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441274	SCV000507618	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421421	SCV000507619	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432068	SCV000507620	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438398	SCV000507621	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422335	SCV000507622	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433025	SCV000507623	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354219	SCV001548776	uncertain significance	Familial ovarian cancer		no assertion criteria provided	clinical testing	The TP53 p.Cys176Tyr variant was identified in dbSNP (ID: rs786202962 as “With Likely pathogenic allele”), ClinVar (classified as likely pathogenic by Ambry Genetics and GeneDx and as uncertain significance by Invitae), Cosmic (identified 111x in large intestine, oesophagus, lung, liver, hematopoietic and lymphoid tissue and predicted to be pathogenic), and in Database of germline p53 mutations. The variant was not identified in GeneInsight-COGR, LOVD 3.0, IARC TP53 Database, or UMD TP53 Mutation databases, nor was it identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant is located in a zinc-binding site within the DNA-binding domain (Pan 2017, Kato 2003, Kang 2013). Assays of the transactivation activity, mRNA expression, and activity of the mutant p53 provide inconsistent data (Epstein 1998, Kang 2013, Mullany 2015). The p.Cys176 residue is conserved across mammals and other organisms, and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University	RCV003995473	SCV004046827	likely pathogenic	Adrenal cortex carcinoma		no assertion criteria provided	clinical testing