Submissions for variant NM_000546.6(TP53):c.817C>T (p.Arg273Cys)

gnomAD frequency: 0.00001  dbSNP: rs121913343

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000205625	SCV000060191	pathogenic	Li-Fraumeni syndrome	2020-08-10	criteria provided, single submitter	clinical testing	The p.Arg273Cys variant in TP53 has been reported in >5 individuals with Li-Fraumeni syndrome (LFS) or LFS-associated tumors (Gonzalez 2009, Janavicius 2011, Masciari 2011, Park 2016, Chan 2018). It has also been identified in 0.005% (1/21592) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 43594). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro and in vivo functional studies provide some evidence that this variant impacts/does not impact protein function (Thukral 1994, Kato 2003, Monti 2011, Li 2014) ; however, these types of assays may not accurately represent biological function. An additional variant involving this codon (p.Arg273Leu) has been identified in individuals with LFS and is classified as pathogenic by this laboratory. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP Criteria applied: PS4, PM5, PS3_Moderate, PM2_Supporting, PP3.
Ambry Genetics	RCV000131966	SCV000187024	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-17	criteria provided, single submitter	clinical testing	The p.R273C pathogenic mutation (also known as c.817C>T), located in coding exon 7 of the TP53 gene, results from a C to T substitution at nucleotide position 817. The arginine at codon 273 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported in multiple families that met classic LFS or Chompret criteria (Janaviius R et al. Breast J. 2011;17(4):409-415; Masciari S et al. Genet. Med. 2011 Jul;13(7):651-7). This alteration is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and a dominant negative phenotype (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100(14):8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). 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 position is characterized as a mutation hotspot and has been shown to be involved in DNA contact and binding (Martin AC et al. Hum. Mutat. 2002 Feb;19(2):149-64). Based on the available evidence, this alteration is classified as a pathogenic mutation.
GeneDx	RCV000254692	SCV000211760	pathogenic	not provided	2023-03-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: loss of growth suppression and apoptotic activities and non-functional transactivation (Kato et al., 2003; Dearth et al., 2007; Malcikova et al., 2010; Monti et al., 2011; Li et al., 2014; Giacomelli et al., 2018; Kotler 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: 11370630, 11315715, 7732013, 28915719, 28527674, 29958926, 27374712, 29489754, 20128691, 16861262, 17606709, 21343334, 21535297, 8479749, 21552135, 24677579, 7887414, 10864200, 11494139, 12695689, 19556618, 20443677, 26681312, 28387325, 28840050, 28717136, 28975465, 30720243, 30092803, 30796655, 30093976, 30840781, 31278746, 31559875, 15510160, 12826609, 35273153, 31105275, 31447099, 29922827, 34906214, 30224644, 29979965, 33245408, 32817165)
Invitae	RCV000205625	SCV000261042	pathogenic	Li-Fraumeni syndrome	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 273 of the TP53 protein (p.Arg273Cys). This variant is present in population databases (rs121913343, gnomAD 0.005%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 8479749, 17606709, 21535297, 21552135). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43594). Advanced modeling performed at Invitae incorporating data from internal and/or published 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, 20128691, 24677579, 29979965, 30224644). This variant disrupts the p.Arg273 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1565144, 8164043, 8479749, 17606709, 18685109, 20693561, 21535297, 21552135, 25584008; Invitae). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000254692	SCV000602279	pathogenic	not provided	2017-07-14	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000144665	SCV000840079	pathogenic	Li-Fraumeni syndrome 1	2017-07-06	criteria provided, single submitter	clinical testing	This c.817C>T (p.Arg273Cys) variant has previously been detected in multiple patients with Li-Fraumeni syndrome or Li-Fraumeni related cancers [PMID 8479749, 21535297, 21552135]. Functional data showed that this variant leads to a severe deficiency of TP53 activity [PMID 21343334, 24677579, 17606709]. The amino acid position 273 of the TP53 protein is a hot spot for pathogenic variants causing Li-Fraumeni syndrome: additional variants affecting the same amino acid at position 273 have been reported (p.Arg273Gly and p.Arg273His). This variant was observed in three heterozygous individuals in the gnomAD database (http://gnomad.broadinstitute.org/variant/17-7577121-G-A). This variant is highly conserved in mammals and computer-based algorithms predict this p.Arg273Cys change to be deleterious. It is thus classified as pathogenic. The next generation sequencing (NGS) reads indicated a skewed mutant to reference allele ratio (about 25% mutant), which was confirmed by Sanger sequencing, indicating mosaicism in this sample. Mosaic somatic pathogenic variants in cancer related genes, including TP53, have been reported in DNA extracted from blood samples in aging populations [PMID 25426837, 25426838, 25326804]. While an increase risk for hematologic cancer was reported in these studies, the clinical significance of these somatic variants in blood is currently unclear. While this variant is a known disease-causing variant observed in patients with Li-Fraumeni syndrome, considering the age of this individual, this finding may result from a somatic event observed in aging process. Studies in another tissue sample such as a skin biopsy is thus suggested to help clarify the clinical significance of this change.
Revvity Omics, Revvity	RCV000254692	SCV002022391	pathogenic	not provided	2021-07-27	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000144665	SCV002525953	pathogenic	Li-Fraumeni syndrome 1	2022-02-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000131966	SCV002582352	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000144665	SCV002583013	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000254692	SCV002585616	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	TP53: PS3, PM1, PM2, PP4, PS4:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000205625	SCV003934643	pathogenic	Li-Fraumeni syndrome	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.817C>T (p.Arg273Cys) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250850 control chromosomes. c.817C>T has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (Masciari_2011, Khincha_2019, Rana_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function shows a severe decrease in promoter binding and transactivation capability ( Monti_2011, Malcikova_2010). The following publications have been ascertained in the context of this evaluation (PMID: 23612969, 21343334, 31212162, 31105275, 21552135, 20128691). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000144665	SCV004047202	pathogenic	Li-Fraumeni syndrome 1		criteria provided, single submitter	clinical testing	The missense variant p.R273C in TP53 (NM_000546.6) has previously been detected in multiple patients with Li-Fraumeni syndrome or Li-Fraumeni related cancers (Eeles et al, 1993). This missense variant causes the same amino acid change as a previously established pathogenic variant. Functional studies reveal that this variant leads to a severe deficiency of TP53 activity (Monti et al, 2011). Experimental studies have shown that this missense change disrupts the DNA-binding, transcriptional transactivation, and tumor suppressor activities of the TP53 protein (Malcikova et al, 2010). The p.R273C variant is observed in 1/18,372 (0.0054%) alleles from individuals of East Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.R273C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 273 of TP53 is conserved in all mammalian species. The nucleotide c.817 in TP53 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003466889	SCV004206237	pathogenic	Adrenocortical carcinoma, hereditary	2023-09-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000144665	SCV004933848	pathogenic	Li-Fraumeni syndrome 1	2024-02-20	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7887414, 9047394, 10864200]. Functional studies indicate this variant impacts protein function [PMID: 8001119, 16861262, 9482117]. This variant is expected to disrupt protein structure [Myriad internal data].
Science for Life laboratory, Karolinska Institutet	RCV000149051	SCV000088693	unknown	Malignant tumor of prostate		no assertion criteria provided	not provided	Converted during submission to Uncertain significance.
Pathway Genomics	RCV000144665	SCV000189996	pathogenic	Li-Fraumeni syndrome 1	2014-07-24	no assertion criteria provided	clinical testing
Database of Curated Mutations (DoCM)	RCV000432002	SCV000504686	likely pathogenic	Hepatocellular carcinoma	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442470	SCV000504687	likely pathogenic	Acute myeloid leukemia	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421090	SCV000504688	not provided	Breast neoplasm	2016-03-10	no assertion provided	literature only
Database of Curated Mutations (DoCM)	RCV000431786	SCV000504689	likely pathogenic	Neoplasm	2015-07-14	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000254692	SCV000692069	pathogenic	not provided		no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785470	SCV000924042	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research