ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.422G>A (p.Cys141Tyr) (rs587781288)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128975 SCV000172861 pathogenic Hereditary cancer-predisposing syndrome 2020-03-19 criteria provided, single submitter clinical testing The p.C141Y pathogenic mutation (also known as c.422G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 422. The cysteine at codon 141 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been reported several times in families either meeting diagnostic criteria for Li-Fraumeni syndrome (LFS) or in families with features suggestive of LFS (Zhou XP et al. Ann Neurol. 1999 Dec;46(6):913-6; Monti P et al. Clin Cancer Res. 2007 Jul 1;13(13):3789-95; Bougeard G et al. J Med Genet. 2008 Aug;45(8):535-8; Ruijs MW et al. J Med Genet. 2010 Jun;47(6):421-8). This mutation is located in the DNA binding domain of the p53 protein and is reported to have loss of transactivation capacity and reduced DNA-binding in yeast-based assays compared to wildtype p53 protein (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Mol Cancer Res. 2011 Mar;9(3):271-9; Malcikova J et al. Biol Chem. 2010 Feb-Mar;391(2-3):197-205). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000472876 SCV000545264 pathogenic Li-Fraumeni syndrome 2020-07-02 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 141 of the TP53 protein (p.Cys141Tyr). 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 (rs587781288, ExAC no frequency). This variant has been reported in individuals affected with Li-Fraumeni syndrome (LFS) related cancers (liposarcoma, astrocytoma, Hodgkin lymphoma) in families with a strong history of LFS-related cancers (PMID: 10589545, 11370630, Invitae). It has also been observed in individuals with breast cancer (PMID: 20522432) and chronic lymphocytic leukemia (PMID: 21232794). ClinVar contains an entry for this variant (Variation ID: 140801). Experimental studies have shown that this missense change disrupts the DNA-binding activity (PMID: 20128691) and transcriptional transactivation activity (PMID: 12826609, 16861262, 21343334, 24256616) of the TP53 protein. For these reasons, this variant has been classified as Pathogenic.
Database of Curated Mutations (DoCM) RCV000427674 SCV000507522 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437920 SCV000507523 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444430 SCV000507524 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427068 SCV000507525 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435449 SCV000507526 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417795 SCV000507527 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428004 SCV000507528 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436530 SCV000507529 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418811 SCV000507530 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429076 SCV000507531 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439333 SCV000507532 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423419 SCV000507533 likely pathogenic Renal cell carcinoma, papillary, 1 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785510 SCV000924082 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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