Submissions for variant NM_000546.6(TP53):c.772G>A (p.Glu258Lys)

dbSNP: rs121912652

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000161071	SCV000211805	pathogenic	not provided	2021-11-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Frebourg 1992, Flaman 1998, Waddell 2001, Kato 2003, Malcikova 2010, Monti 2011, Kotler 2018); Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15722483, 11593407, 30720243, 21343334, 17606709, 9364015, 7829527, 1458490, 10719737, 21121188, 7732013, 8252037, 10753186, 11429705, 16492679, 9546439, 9635858, 1631137, 21232794, 8570655, 14559903, 12909720, 8313374, 29625052, 29979965, 21552135, 30840781, 30577483, 33309985, 15510160, 1978757, 20128691)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000161071	SCV000602278	pathogenic	not provided	2021-10-06	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in affected individuals with Li-Fraumeni Syndrome, glioblastoma, gastric, brain, and colon cancers (PMIDs: 29625052 (2018), 26425688 (2015), 21552135 (2011), 17606709 (2007), and 1978757 (1990)). Functional studies showed severe deficiencies in DNA binding and transactivation of transcriptional targets (PMIDs: 21343334 (2011) and 20128691 (2010)). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000772122	SCV000905196	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-14	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 258 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein to be non-functional and exhibit dominant negative effect in transactivation assays (PMID: 12826609, 16492679, 20128691, 21343334) and in cell growth assays (PMID: 29979965, 30224644). This variant has been reported in individuals affected with Li-Fraumeni syndrome (PMID: 9667734, 10922393, 1978757, 21552135). This variant has been identified in 1/246228 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792895	SCV000932221	pathogenic	Li-Fraumeni syndrome	2024-05-18	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 258 of the TP53 protein (p.Glu258Lys). This variant is present in population databases (rs121912652, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 1978757, 9667734, 10922393, 17606709, 21552135, 29625052, 34529667; Invitae). ClinVar contains an entry for this variant (Variation ID: 12348). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 20128691, 21343334, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000772122	SCV001189203	pathogenic	Hereditary cancer-predisposing syndrome	2024-11-11	criteria provided, single submitter	clinical testing	The p.E258K pathogenic mutation (also known as c.772G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 772. The glutamic acid at codon 258 is replaced by lysine, an amino acid with similar properties. The p.E258K variant was first reported in a patient diagnosed with breast cancer at 34 whose tumor demonstrated loss of heterozygosity (LOH), and whose family met classic LFS criteria with a history of early onset sarcomas, and brain tumors (Malkin D et al. Science. 1990 Nov;250:1233-8). This variant has also been reported in a family with a strong history of gastric cancers, and in an individual with glioblastoma multiforme (Masciari S et al. Genet. Med. 2011 Jul;13:651-7; Huang KL et al. Cell, 2018 04;173:355-370.e14). Yeast based functional studies showed this alteration to have loss of transactivation capacity, and dominant negative effect (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9). Studies on this variant conducted in mammalian cells showed inability to suppress growth, and a protein binding profile indicative of a mutant protein conformation (Frebourg T et al. Proc. Natl. Acad. Sci. U.S.A., 1992 Jul;89:6413-7). Additional studies conducted in human cell lines also 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 variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genome-Nilou Lab	RCV000772122	SCV002582357	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000013141	SCV002583018	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
OMIM	RCV000013141	SCV000033388	pathogenic	Li-Fraumeni syndrome 1	1990-11-30	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000582699	SCV000692070	uncertain significance	not specified		no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785291	SCV000923859	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research