ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.423C>G (p.Cys141Trp) (rs1057519977)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467641 SCV000545329 uncertain significance Li-Fraumeni syndrome 2018-09-20 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 141 of the TP53 protein (p.Cys141Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with childhood osteosarcoma (PMID: 29946497). ClinVar contains an entry for this variant (Variation ID: 376564). Experimental studies in yeast have shown that this missense change results in compromised TP53 transactivation activity (PMID: 12826609, 20407015). This variant disrupts the p.Cys141Tyr amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 12826609, 10589545, 11370630), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.
Ambry Genetics RCV000492201 SCV000581134 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-15 criteria provided, single submitter clinical testing The p.C141W variant (also known as c.423C>G), located in coding exon 4 of the TP53 gene, results from a C to G substitution at nucleotide position 423. The cysteine at codon 141 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based assays and is predicted to affect several p53 isoforms (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003;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). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Database of Curated Mutations (DoCM) RCV000430241 SCV000507534 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440499 SCV000507535 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422816 SCV000507536 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434797 SCV000507537 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442353 SCV000507538 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423924 SCV000507539 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434169 SCV000507540 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444942 SCV000507541 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424802 SCV000507542 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431589 SCV000507543 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445034 SCV000507544 likely pathogenic Renal cell carcinoma, papillary, 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425931 SCV000507545 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only

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