Submissions for variant NM_000546.6(TP53):c.358A>G (p.Lys120Glu)

dbSNP: rs121912658

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129457	SCV000184227	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-02	criteria provided, single submitter	clinical testing	The p.K120E pathogenic mutation (also known as c.358A>G), located in coding exon 3 of the TP53 gene, results from an A to G substitution at nucleotide position 358. The lysine at codon 120 is replaced by glutamic acid, an amino acid with 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). Studies conducted in human cell lines indicate this alteration is deficient 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). Internal structural analysis shows K120E is located in the same groove as several other known likely pathogenic variants and perturbs the structure with equivalent energies and greater energies (Ambry internal data). 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.
GeneDx	RCV000213049	SCV000211797	likely pathogenic	not provided	2020-11-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: loss of transactivation, growth suppression, and apoptotic activities (Resnick 2003, Kato 2003, Sykes 2006, Pietsch 2008, Monteith 2016, Kotler 2018); Not observed 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: 29979965, 15138567, 12909720, 12826609, 14559903, 17189187, 18524770, 27341992)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000696142	SCV000824690	uncertain significance	Li-Fraumeni syndrome	2025-01-15	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 120 of the TP53 protein (p.Lys120Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with osteosarcoma (PMID: 32191290). ClinVar contains an entry for this variant (Variation ID: 141098). Invitae Evidence Modeling incorporating data from in vitro 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, 29979965, 30224644). 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.
Myriad Genetics, Inc.	RCV004019730	SCV004932429	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-13	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 18524770, 24814347, 29979965].
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785522	SCV000924094	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research