Submissions for variant NM_000546.6(TP53):c.473G>C (p.Arg158Pro)

dbSNP: rs587782144

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236862	SCV000293524	likely pathogenic	not provided	2018-11-13	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.473G>C at the cDNA level, p.Arg158Pro (R158P) at the protein level, and results in the change of an Arginine to a Proline (CGC>CCC). This variant has been observed in at least one individual reported to have Li-Fraumeni syndrome (Morgan 2010). On functional interrogation, TP53 Arg158Pro has been shown to impact transactivation, growth suppression, and cause a dominant-negative effect (Brachmann 1996, Dearth 2007, Kotler 2018). Consistent with these results, this variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Arg158Pro was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider TP53 Arg158Pro to be a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000548853	SCV000629825	likely pathogenic	Li-Fraumeni syndrome	2022-02-17	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, 30224644). 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: 246118). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 20127978; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 158 of the TP53 protein (p.Arg158Pro).
Mendelics	RCV000989719	SCV001140261	likely pathogenic	Squamous cell carcinoma of the head and neck	2019-05-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288932	SCV002582390	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288931	SCV002583052	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288931	SCV004931212	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-14	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
Ambry Genetics	RCV002288932	SCV005522112	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-17	criteria provided, single submitter	clinical testing	The p.R158P pathogenic mutation (also known as c.473G>C), located in coding exon 4 of the TP53 gene, results from a G to C substitution at nucleotide position 473. The arginine at codon 158 is replaced by proline, an amino acid with dissimilar properties. This alteration has been reported in a Li Fraumeni syndrome family (Morgan JE et al. Hum Mutat, 2010 Apr;31:484-91). It has also been reported in a pediatric patient meeting Chompret criteria with a personal history of rhabdomyosarcoma and osteosarcoma (Penkert J et al. J Hematol Oncol, 2022 Aug;15:107). This alteration has also been reported in a patient with acute myeloid leukemia (Zuo Z et al. Leuk Res Rep, 2023 Aug;20:100385). 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 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.