ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.817C>T (p.Arg273Cys) (rs121913343)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000205625 SCV000060191 likely pathogenic Li-Fraumeni syndrome 2010-08-05 criteria provided, single submitter clinical testing The Arg273Cys variant has been reported in the literature in one individual with clinical features consistent with Li-Fraumeni Syndrome (LFS, Gonzales 2009). Th is individual had cancer as a teenager followed by two additional cancers in the ir twenties. Two other variants at the same amino acid position (Arg273His and A rg273Leu) have also been identified in individuals with features of LFS, and one of these variants was shown to have occurred de novo in a proband (Gonzalez 200 9). The Arg273Cys variant is the most common somatic mutation listed in the Cata logue of Somatic Mutations in Cancer (www.sanger.ac.uk/cosmic/) and this change is found in tumors throughout the body, including the central nervous system (10 tumors), haematopoietic and lymphoid tissue (5), bone (3), large intestine (2), and ovaries (1). Arg273 is highly conserved across divergent species and three bioinformatic algorithms predict this variant to affect protein function. Theref ore, this variant is likely to be pathogenic.
Ambry Genetics RCV000131966 SCV000187024 pathogenic Hereditary cancer-predisposing syndrome 2017-08-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position,Deficient protein function in appropriate functional assay(s),Structural Evidence
GeneDx RCV000254692 SCV000211760 pathogenic not provided 2018-07-24 criteria provided, single submitter clinical testing This variant is denoted TP53 c.817C>T at the cDNA level, p.Arg273Cys (R273C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been reported in multiple individuals meeting Chompret criteria or with early-onset Li-Fraumeni related cancers (Eeles 1993, Frebourg 1995, Chompret 2000, Nutting 2000, Bougeard 2001, Pepper 2003, Gonzalez 2009, Kim 2010, Janavicius 2011, Masciari 2011, Park 2016, Meiss 2018). Multiple functional studies have found this variant to impact cell proliferation and apoptosis as well as binding and transactivation of known TP53 response elements (Dearth 2007, Malcikova 2010, Monti 2011, Li 2014). 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 Arg273Cys was not observed at a significant allele frequency 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 the current evidence, we consider this variant to be pathogenic.
Invitae RCV000205625 SCV000261042 pathogenic Li-Fraumeni syndrome 2019-01-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 273 of the TP53 protein (p.Arg273Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs121913343, ExAC 0.002%). This variant has been observed in individuals and families affected with Li-Fraumeni syndrome (LFS), and has been shown to segregate with disease in affected families (PMID: 17606709, 8479749, 21535297, 21552135). ClinVar contains an entry for this variant (Variation ID: 43594). Experimental studies have shown that this missense change disrupts the DNA-binding, transcriptional transactivation, and tumor suppressor activities of the TP53 protein (PMID: 20128691, 12826609, 24677579). 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.
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 Neoplasm of the breast 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 Genetic Testing Laboratories,Mayo Clinic RCV000254692 SCV000692069 pathogenic not provided no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785470 SCV000924042 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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