ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.404G>A (p.Cys135Tyr) (rs587781991)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130396 SCV000185255 pathogenic Hereditary cancer-predisposing syndrome 2020-10-05 criteria provided, single submitter clinical testing The p.C135Y pathogenic mutation (also known as c.404G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 404. The cysteine at codon 135 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been reported in one Chinese patient diagnosed with sporadic triple negative breast cancer. This individual also carried a likely pathogenic variant in the MSH6 gene (Yi D et al. Hum. Genomics. 2019 01;13:4). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. <span style="font-style: italic;">Cancer Discov. 2018 02;8:174-183). The p.C135Y variant is located in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and dominant negative activity in yeast based assays (Dearth LR et al. Carcinogenesis. 2007 Feb; 28(2):289-98; Jordan JJ et al. Mol. Cancer Res. 2010 May;8(5):701-16; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). 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). In addition, internal structural analysis suggests this variant, which is a buried residue in the secondary shell of the DNA binding surface, is structurally destabilizing (Cho Y et al. Science. 1994 Jul 15;265(5170):346-55; Ambry internal data). 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 Health, Inc RCV000130396 SCV000686738 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing
Invitae RCV001069143 SCV001234291 uncertain significance Li-Fraumeni syndrome 2020-05-30 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 404 of the TP53 protein (p.Cys135Tyr). 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 in an individual affected with breast cancer at an allele fraction of 0.16 who also had a germline variant in MSH6 (PMID: 30630526). ClinVar contains an entry for this variant (Variation ID: 141762). This variant has been reported to affect TP53 protein function (PMID: 12826609, 21470402, 22847613, 8336941,7651740, 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000581322 SCV001335063 pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000419337 SCV000507444 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430048 SCV000507445 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437052 SCV000507446 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419825 SCV000507447 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428748 SCV000507448 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439440 SCV000507449 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422242 SCV000507450 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429447 SCV000507451 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438381 SCV000507452 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421166 SCV000507453 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431855 SCV000507454 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444676 SCV000507455 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423651 SCV000507456 likely pathogenic Adrenocortical carcinoma 2016-05-31 no assertion criteria provided literature only
Mayo Clinic Laboratories, Mayo Clinic RCV000581322 SCV000692089 likely pathogenic not provided no assertion criteria provided clinical testing

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