ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.821T>A (p.Val274Asp)

dbSNP: rs1057520006
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001229449 SCV001401894 uncertain significance Li-Fraumeni syndrome 2021-05-17 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 376675). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with aspartic acid at codon 274 of the TP53 protein (p.Val274Asp). The valine residue is highly conserved and there is a large physicochemical difference between valine and aspartic acid. Experimental studies have shown that this variant affects TP53 protein function (PMID: 12826609, 30224644, 29979965). 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 RCV003168618 SCV003912001 pathogenic Hereditary cancer-predisposing syndrome 2023-02-03 criteria provided, single submitter clinical testing The p.V274D pathogenic mutation (also known as c.821T>A), located in coding exon 7 of the TP53 gene, results from a T to A substitution at nucleotide position 821. The valine at codon 274 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (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 and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Two other alterations at the same codon, p.V274G (c.821T>G) and p.V274F (c.820G>T), have been also been shown to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9), and are deficient at growth suppression and have a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387), as well as have a deleterious structural impact (Cho Y et a. Science. 1994 Jul; 265(5170):346-55). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well 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.
Database of Curated Mutations (DoCM) RCV000434236 SCV000510013 likely pathogenic Prostate adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441480 SCV000510014 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424200 SCV000510015 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431443 SCV000510016 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443884 SCV000510017 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424885 SCV000510018 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432106 SCV000510019 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443016 SCV000510020 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425563 SCV000510021 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436477 SCV000510022 likely pathogenic Ovarian serous cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419239 SCV000510023 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only

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