ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.421T>C (p.Cys141Arg)

dbSNP: rs1057519978
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001861481 SCV002115732 uncertain significance Li-Fraumeni syndrome 2022-10-17 criteria provided, single submitter clinical testing 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. This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 141 of the TP53 protein (p.Cys141Arg). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). 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. ClinVar contains an entry for this variant (Variation ID: 376565).
Ambry Genetics RCV002328907 SCV002629030 likely pathogenic Hereditary cancer-predisposing syndrome 2020-06-29 criteria provided, single submitter clinical testing The p.C141R variant (also known as c.421T>C), located in coding exon 4 of the TP53 gene, results from a T to C substitution at nucleotide position 421. The cysteine at codon 141 is replaced by arginine, 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 in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). 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). Based on internal structural analysis, C141R is highly destabilizing to the local structure and considered deleterious (Ambry internal data; Natan E et al. J. Mol. Biol. 2011 Jun;409(3):358-68). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Database of Curated Mutations (DoCM) RCV000436190 SCV000507546 likely pathogenic Prostate adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418678 SCV000507547 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425407 SCV000507548 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437414 SCV000507549 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419723 SCV000507550 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430017 SCV000507551 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440220 SCV000507552 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420817 SCV000507553 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431037 SCV000507554 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441312 SCV000507555 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423623 SCV000507556 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432161 SCV000507557 likely pathogenic Papillary renal cell carcinoma type 1 2016-05-31 no assertion criteria provided literature only

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