Submissions for variant NM_000546.6(TP53):c.818G>T (p.Arg273Leu)

dbSNP: rs28934576

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000568814	SCV000665156	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-12	criteria provided, single submitter	clinical testing	The p.R273L pathogenic mutation (also known as c.818G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 818. The arginine at codon 273 is replaced by leucine, an amino acid with dissimilar properties. This mutation occurs at a well-characterized mutation "hotspot" located within the functionally critical DNA binding domain. Several other mutations have been described at this position and are associated with a classic LFS-associated tumor spectrum (Petitjean A et al. IARC TP53 database [version R16, November 2012]. Hum Mutat. 2007 Jun;28(6):622-9). This specific alteration has been reported in a family meeting Chompret criteria for Li-Fraumeni Syndrome, and has been identified as a de novo mutation in a patient diagnosed with adrenaocortical carcinoma and rhabdomyosarcoma at 1 year of age (Bougeard Get al. J. Clin. Oncol. 2015 Jul; 33(21):2345-52; Chompret A et al. Br. J. Cancer 2000 Jun; 82(12):1932-7). Functional assays conducted in both yeast and human cells have shown a loss of transactivation capacity and a dominant negative phenotype (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti, P et al. Mol Cancer Res. 2011 Mar;9(3):271-9; Dearth Let al. Carcinogenesis 2007 Feb; 28(2):289-98). 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). Based on crystal structure analysis, this position has been shown to be involved in DNA contact and binding (Martin A et al. Hum. Mutat. 2002 Feb; 19(2):149-64). 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 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 available evidence, p.R273L is classified as a pathogenic mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000822080	SCV000962866	pathogenic	Li-Fraumeni syndrome	2024-09-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 273 of the TP53 protein (p.Arg273Leu). This variant is present in population databases (rs28934576, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni-associated cancers (PMID: 10864200, 26014290). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376655). 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: 9407971, 12826609, 21343334, 29979965, 30224644). This variant disrupts the p.273 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1565144, 9242456, 17540308, 20693561, 21484931, 21552135). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001539823	SCV001757640	pathogenic	not provided	2022-12-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of apoptotic activity, and exhibits a dominant-negative effect (Monti et al., 2007; Monti et al., 2011; Giacomelli et al., 2018; Kotler et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); 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: 10519380, 16322298, 9738975, 12792784, 16000567, 8336941, 10753186, 9546439, 8062826, 11429705, 30840781, 15510160, 29922827, 9407971, 17606709, 21343334, 30720243, 29752319, 10864200, 29092957, 17311302, 32658383, 16861262, 21484931, 21552135, 8649776, 17540308, 15161705, 27813088, 15037740, 11793474, 9242456, 30224644, 26619011, 20693561, 12826609, 1565144, 29979965, 26014290)
Genome-Nilou Lab	RCV000568814	SCV002582451	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289534	SCV002583113	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002502455	SCV002784210	pathogenic	Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma; Colorectal cancer; Bone marrow failure syndrome 5	2022-05-24	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000822080	SCV004848115	pathogenic	Li-Fraumeni syndrome	2017-09-11	criteria provided, single submitter	clinical testing	The p.Arg273Leu variant in TP53 has been reported in 6 individuals with TP53-associated cancers, including 1 that was de novo (paternity- confirmed; Chompret 2000, Kyritsis 1994, Monti 2007, Dong 2011 and Bougeard 2015). This variant has also been reported in ClinVar (Variation ID 376655) and has been identified in 1/111470 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28934576), though the allele ratio suggests it may be somatic. Arginine at position 273 is a mutational hotspot in many different types of cancers, and different changes at the same codon (p.Arg273Cys and p.Arg273His) have been reported in multiple families with Li-Fraumeni syndrome. Computational prediction tools suggest that the p.Arg273Leu variant may impact the protein. In vitro functional studies provide some evidence that the p.Arg273Leu variant may impact protein function (Kawamura 1996, Monti 2011, Ory 1994). In summary, the p.Arg273Leu variant is pathogenic Li-Fraumeni syndrome in an autosomal dominant inheritance.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785524	SCV000924096	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research