Submissions for variant NM_000546.6(TP53):c.530C>G (p.Pro177Arg)

dbSNP: rs751477326

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540639	SCV000629833	pathogenic	Li-Fraumeni syndrome	2024-09-08	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 177 of the TP53 protein (p.Pro177Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 20421238, 26787237, 27501770; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 458547). 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, 27873457, 30224644). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000565979	SCV000665324	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-24	criteria provided, single submitter	clinical testing	The p.P177R variant (also known as c.530C>G), located in coding exon 4 of the TP53 gene, results from a C to G substitution at nucleotide position 530. The proline at codon 177 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in a 31-year-old patient with adrenocortical carcinoma; a patient with breast cancer at age 34 and family history suggestive of Li-Fraumeni syndrome (LFS); a family affected with osteosarcoma, melanoma, chordoma, dysembryoplastic neuroepithelial tumor, chondroma, and colorectal cancer; and a patient with colorectal cancer at age 21; and in pediatric acute lymphoblastic leukemia and hereditary cancer panel testing cohorts (Ide H et al. Jpn. J. Clin. Oncol. 2010 Aug;40:815-8; Meric-Bernstam F et al. Ann. Oncol. 2016 May;27:795-800; Villani A et al. Lancet Oncol. 2016 Sep;17(9):1295-305; Rengifo-Cam W et al. Clin. Gastroenterol. Hepatol. 2018 Jan;16(1):140-141; Qian M et al. J. Clin. Oncol. 2018 Feb;36(6):591-599; Rana HQ et al. Genet Med, 2019 11;21:2478-2484). This variant is in the DNA binding domain of the TP53 protein and reported to have loss of transactivation capacity in multiple yeast functional studies (Kato S et al. Proc. Natl. Acad. Sci. U.S.A. 2003 Jul;100:8424-9; Shi XB et al. BJU Int. 2004 Nov;94:996-1002). 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). Structural analysis has shown that this alteration lies in a region of the protein surface that interacts with the C terminal BRCT1 domain and causes a steric clash, destabilizing that protein-protein interaction (Shi Z et al. J. Mol. Biol. 2011 Oct;413:495-512). 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 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	RCV000582953	SCV001764203	pathogenic	not provided	2023-07-06	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression activity (Kato et al., 2003; Giacomelli et al., 2018; Kotler et al., 2018); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene in published literature (Ide et al., 2010; Abegglen et al., 2015; Villani et al., 2016; Meric-Bernstam et al., 2016; Rengifo-Cam et al., 2017; Qian et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11051241, 7732013, 12826609, 29979965, 22915647, 21763698, 28272845, 29300620, 32722340, 29866652, 17312569, 20421238, 26787237, 21118481, 23973117, 24140581, 24448499, 11161385, 26003295, 12872257, 18969416, 15369332, 22483214, 24213701, 22479694, 29026176, 22170717, 26447779, 15541116, 28624650, 27501770, 32704382, 37377903, 30224644, 15510160, 32817165, 31105275, 34863587, 30840781, 30720243)
Genome-Nilou Lab	RCV000565979	SCV002582384	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289734	SCV002583046	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002289734	SCV004932164	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].
Mayo Clinic Laboratories, Mayo Clinic	RCV000582953	SCV000692082	pathogenic	not provided		no assertion criteria provided	clinical testing