Submissions for variant NM_000546.6(TP53):c.524G>T (p.Arg175Leu)

dbSNP: rs28934578

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000810785	SCV005201130	likely pathogenic	Li-Fraumeni syndrome	2024-09-06	reviewed by expert panel	curation	The NM_000546.6: c.524G>T variant in TP53 is a missense variant predicted to cause substitution of arginine by leucine at amino acid 175 (p.Arg175Leu). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in 4 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 2 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; PMID: 16707427; Internal lab contributors: Invitae, Ambry). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644).Computational predictor scores (BayesDel = 0.57303; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). At least one individual with this variant was found to have a variant allele fraction of ≤35%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor: Invitae). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157). Another missense variant(c.524G>A, p.Arg175His) (ClinVar Variation ID: 12374), in the same codon has been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Moderate, PM2_Supporting, BS3_Supporting, PP3_Moderate, PP4, PM1, PM5 (Bayesian Points: 9; VCEP specifications version 2.0; 9/6/2024)
Ambry Genetics	RCV000161065	SCV000275440	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-17	criteria provided, single submitter	clinical testing	The p.R175L pathogenic mutation (also known as c.524G>T), located in coding exon 4 of the TP53 gene, results from a G to T substitution at nucleotide position 524. The arginine at codon 175 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been identified in pediatric patients with adrenal cortical carcinoma and in families meeting Chompret criteria for Li-Fraumeni syndrome (West AN et al. Cancer Res. 2006 May; 66(10):5056-62; Ambry internal data). This alteration is located in the DNA binding domain and has shown a partial loss of transactivation activity, and temperature sensitivity in yeast and mammalian cell in vitro assays (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Shiraishi K et al. J. Biol. Chem. 2004 Jan; 279(1):348-55; Dearth LR et al. Carcinogenesis 2007 Feb; 28(2):289-98). More extensive evaluation of this variant showed that it was able to suppress cell growth similar to wild type p53, yet was deficient in apoptotic activity (West AN et al. Cancer Res. 2006 May; 66(10):5056-62). Structural modeling by this same group determined that the leucine substitution may destabilize the native structure, yet not necessarily disrupt the overall conformation of the DNA binding domain. Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Another alteration at this same position, p.R175H, is a well-characterized mutation hotspot known to be associated with classic Li-Fraumeni syndrome (McIntyre et al. J Clin Oncol. 1994. 12(5):925-930; Melhem-Bertrandt et al. Cancer. 2012. 118(4):908-13; Choong et al. Clin Genet. 2012. 82(6):564-8; Varley et al. J Med Genet. 1995. 32:942-945). This variant was not reported in population-based 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810785	SCV000951018	pathogenic	Li-Fraumeni syndrome	2022-08-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg175 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8164043, 8825920, 11370630, 21761402, 22006311, 25927356). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 16707427, 16861262). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 182963). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 16707427; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 175 of the TP53 protein (p.Arg175Leu).
Genome-Nilou Lab	RCV000161065	SCV002582385	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288703	SCV002583047	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing