ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.473G>A (p.Arg158His) (rs587782144)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130708 SCV000185595 pathogenic Hereditary cancer-predisposing syndrome 2019-01-25 criteria provided, single submitter clinical testing The p.R158H pathogenic mutation (also known as c.473G>A) is located in coding exon 4 of the TP53 gene. This alteration results from a G to A substitution at nucleotide position 473. The arginine at codon 158 is replaced by histidine, an amino acid with some highly similar properties. This alteration has been reported in multiple individuals with clinical histories suspicious for Li-Fraumeni syndrome, with ages of onset ranging from childhood to adulthood (Varley JM et al. Am J Hum Genet. 1999; 65:995-1006; Villani A et al. Lancet Oncol. 2011 Jun;12(6):559-67; Mitchell G et al. PLoS One. 2013 Jul 22;8(7):e69026; Ruijs MW et al. J Med Genet. 2010 Jun;47(6):421-8; Bougeard GJ et al. J Med Genet. 2008 Aug;45(8):535-8; Wasserman JD et al. J. Clin. Oncol. 2015 Feb;33:602-9; Zerdoumi Y et al. Hum. Mol. Genet. 2017 Jul;26(14):2812; Stjepanovic N et al. BMC Med Genomics. 2018 Aug;11(1):65). In a study of 214 French families with Li-Fraumeni syndrome, this alteration was identified in eight families; six of these families had cases of adrenocortical carcinoma (Bougeard G et al. J. Clin. Oncol., 2015 Jul;33:2345-52). This alteration is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based studies (IARC TP53 database; 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). In addition, a recent functional study demonstrated that the reduction in transcriptional activity and DNA binding resulting from this amino acid substitution is similar to that observed in null mutations (Zerdoumi Y et al. Hum. Mol. Genet. 2017 Jul;26(14):2812). Furthermore, three different TP53 missense mutations at the same codon have been reported to be associated with Li-Fraumeni syndrome: p.R158G, p.R158P, and p.R158C (Chompret A et al. Br J Cancer. 2000; 82(12):1932-7; Morgan JE et al. Hum Mutat. 2010;31(4):484-91; Herrmann LJ et al. J Clin Endocrinol Metab. 2012 Mar;97(3):E476-85). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000227859 SCV000285199 pathogenic Li-Fraumeni syndrome 2020-10-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 158 of the TP53 protein (p.Arg158His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs587782144, ExAC 0.002%). This variant has been reported in individuals affected with TP53-related cancers (PMID: 10486318, 23894400, 20455025, 24764719, 26014290, 23175693), and in several Li-Fraumeni families (PMID: 20522432, 17606709, 21601526, 18685109). This variant is also known as c.12407G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 141963). Experimental studies using model organisms and mammalian cells have shown that this missense change disrupts TP53 protein function (PMID: 25584008, 21343334, 10229196, 12826609). Several different missense changes involving this codon (p.Arg158Leu, p.Arg158Gly, p.Arg158Cys) have been reported in individuals with TP53-related conditions (PMID: 25234657, 10864200, 22170717, 21339461, 21343334), indicating that this amino acid is important for TP53 function. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000255654 SCV000322153 pathogenic not provided 2018-07-19 criteria provided, single submitter clinical testing This variant is denoted TP53 c.473G>A at the cDNA level, p.Arg158His (R158H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has been observed in multiple individuals meeting Li-Fraumeni diagnostic or Chompret criteria (Varley 1999, Ruijs 2010, Mitchell 2013, Raymond 2013, Wong 2014, Bougeard 2015, Villani 2016) and others with Li-Fraumeni-spectrum cancers (Melhem-Bertrandt 2012, Qian 2018). TP53 Arg158His has also been identified in individuals whose personal histories are inconsistent with Li-Fraumeni syndrome (Robertson 2010, Ceelen 2011), leading Bougeard et al. (2015) to suggest this variant might cause reduced penetrance of Li-Fraumeni-related tumors apart from adrenocortical carcinoma, similar to the TP53 Arg337His Brazilian founder variant. Functional studies have produced variable results. The International Agency for Research on Cancer TP53 database lists TP53 Arg158His as having non-functional transactivation activity based on assays by Kato et al. (2003), consistent with the strong impact on transactivation reported by Smith et al. (1999), while higher levels of transactivation and no dominant-negative effect have been reported in other studies (Campomenosi 2001, Monti 2011, Wasserman 2015). Additionally, cells transfected with TP53 Arg158His demonstrated intermediate levels of growth suppression and colony reduction in comparison to wild-type or other pathogenic variants (Smith 1999, Wasserman 2015, Kotler 2018). TP53 Arg158His was not observed at a significant 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 currently available evidence, we consider TP53 Arg158His to be pathogenic.
Color Health, Inc RCV000130708 SCV000537627 likely pathogenic Hereditary cancer-predisposing syndrome 2019-12-13 criteria provided, single submitter clinical testing
UCLA Clinical Genomics Center, UCLA RCV000496787 SCV000588155 pathogenic Li-Fraumeni syndrome 1 2013-12-10 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000227859 SCV000713289 pathogenic Li-Fraumeni syndrome 2020-02-13 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Counsyl RCV000496787 SCV000785720 likely pathogenic Li-Fraumeni syndrome 1 2017-11-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000227859 SCV001360868 pathogenic Li-Fraumeni syndrome 2019-10-24 criteria provided, single submitter clinical testing Variant summary: TP53 c.473G>A (p.Arg158His) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the p53 protein. 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 4e-06 in 251268 control chromosomes (gnomAD). c.473G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (LFS) or LFS spectrum tumors (e.g. Varley_1999, Bougeard_2008, Ceelen_2011); and at least one of these reports described co-segregation of the variant with Li-Fraumeni Syndrome in one family (Ceelen_2011). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function and demonstrated reduced overall transcription activity (TA) on several different promoters (e.g. Monti_2011, Wasserman_2015). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Several different missense changes involving this codon (p.Arg158Leu, p.Arg158Gly, p.Arg158Cys, Arg158Pro) have been reported in individuals with TP53-related conditions (HGMD), indicating that this amino acid is important for TP53 function. Based on the evidence outlined above, the variant was classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000227859 SCV001434921 pathogenic Li-Fraumeni syndrome 2018-08-13 criteria provided, single submitter clinical testing The c.473G>A (p.Arg158His) variant in the TP53 gene has been reported in mulitple patients/families with cancers (PMID 10486318, 17308077, 20522432, 21552135, 21761402, 23175693, 23894400 and 24764719). This variant is observed with a low minor allele frequency in the gnomAD database (1/246110). This variant is at a mutation hotspot of the DNA binding domain where other pathogenic variants in the nearby region have been reported. Functional studies demonstrated decrease P53 functionality (PMID 17606709, 21343334 and 28472496). Therefore, the c.473G>A (p.Arg158His) variant in the TP53 gene is classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000255654 SCV001448119 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000255654 SCV000692086 pathogenic not provided no assertion criteria provided clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001257522 SCV001434348 pathogenic Rhabdomyosarcoma (disease) 2020-09-01 no assertion criteria provided provider interpretation

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