Submissions for variant NM_000546.6(TP53):c.843C>A (p.Asp281Glu)

dbSNP: rs1057519984

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470818	SCV000545278	likely pathogenic	Li-Fraumeni syndrome	2021-11-08	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 406568). This missense change has been observed in individual(s) with sarcoma (PMID: 23894400, 27493922). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 281 of the TP53 protein (p.Asp281Glu).
CeGaT Center for Human Genetics Tuebingen	RCV000658764	SCV000780558	likely pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	TP53: PS1, PM2, PS3:Moderate
Ambry Genetics	RCV002446795	SCV002677815	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-01-20	criteria provided, single submitter	clinical testing	The p.D281E variant (also known as c.843C>A), located in coding exon 7 of the TP53 gene, results from a C to A substitution at nucleotide position 843. The aspartic acid at codon 281 is replaced by glutamic acid, an amino acid with highly similar 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). This alteration has been identified in a family meeting criteria for Li-Fraumeni syndrome; of note, an alteration in PTEN (designated as IVS1-1G>A) was also identified in this family (Akouchekian M et al. Med J Islam Repub Iran 2016 May;30:378). This alteration has also been identified in a 19-year-old proband with osteosarcoma (Mitchell G et al. PLoS ONE 2013 Jul;8(7):e69026). 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). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). 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.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000499361	SCV000590904	uncertain significance	Carcinoma of colon	2015-07-16	flagged submission	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785325	SCV000923893	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research