ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.527G>A (p.Cys176Tyr) (rs786202962)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166045 SCV000216806 pathogenic Hereditary cancer-predisposing syndrome 2019-11-21 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 likely pathogenic not provided 2017-01-20 criteria provided, single submitter clinical testing This variant is denoted TP53 c.527G>A at the cDNA level, p.Cys176Tyr (C176Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGC>TAC) in exon 5. This variant has not, to our knowledge, been reported in the literature in association with Li-Fraumeni syndrome. However, TP53 Cys176Tyr is reported to be a frequently occurring somatic mutation in various cancers, including but not limited to breast, ovarian, brain, colon, and lung cancer (Brachmann 2004, Kang 2013, Pan 2014). Additionally, this variant has been found to bind/stabilize Zn1 and via a yeast based assay eliminate activation of the MCK, mdm-2, and WAF1 enhancers (Epstein 1998, Joerger 2010, Eldar 2013). TP53 Cys176Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Cys176Tyr alters a position that is conserved across species and is located within the DNA binding domain, is a Zinc-binding site, and with a region responsible for interaction with HIPK1, AXIN1, ZNFG385A, and FBXO42 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider TP53 Cys176Tyr to be a variant, expected pathogenic.
Invitae RCV000461158 SCV000545328 pathogenic Li-Fraumeni syndrome 2020-08-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 176 of the TP53 protein (p.Cys176Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with adrenocortical carcinoma (PMID: 29070607). ClinVar contains an entry for this variant (Variation ID: 186451). Experimental studies in yeast have shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609, 9572492). For these reasons, this variant has been classified as Pathogenic.
Database of Curated Mutations (DoCM) RCV000435778 SCV000507609 likely pathogenic Renal cell carcinoma, papillary, 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 Adenocarcinoma of stomach 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 Adenocarcinoma of prostate 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.

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