Submissions for variant NM_000546.6(TP53):c.871A>G (p.Lys291Glu)

dbSNP: rs1555525126

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000575139	SCV000664928	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-06	criteria provided, single submitter	clinical testing	The p.K291E variant (also known as c.871A>G), located in coding exon 7 of the TP53 gene, results from an A to G substitution at nucleotide position 871. The lysine at codon 291 is replaced by glutamic acid, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein, was not found to have an effect on transactivation capacity, but is predicted to affect several p53 isoforms (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). In addition, this variant was shown to induce apoptosis at rates higher than wild-type, however there was no evidence that this alteration had an effect on the protein's ability to transactivate TP53 target genes (Kakudo Y et al. Cancer Res. 2005 Mar 15;65(6):2108-14). Studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no 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 amino acid position is well conserved in available vertebrate species; however, glutamic acid is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000806261	SCV000946250	uncertain significance	Li-Fraumeni syndrome	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 291 of the TP53 protein (p.Lys291Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 480951). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 15781620). 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.
Genome-Nilou Lab	RCV000575139	SCV002581987	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289802	SCV002583099	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003459311	SCV004206268	uncertain significance	Adrenocortical carcinoma, hereditary	2023-06-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000806261	SCV004843732	uncertain significance	Li-Fraumeni syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 291 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant is functional in yeast transcriptional transactivation, human cell growth suprression and proliferation, and apoptosis induction assays (PMID: 15781620, 12826609, 29979965, 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.