ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs587782144
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Total submissions: 24
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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 2022-02-11 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). 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). 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). 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.
Invitae RCV000227859 SCV000285199 pathogenic Li-Fraumeni syndrome 2024-01-19 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 158 of the TP53 protein (p.Arg158His). This variant is present in population databases (rs587782144, gnomAD 0.01%). This missense change has been observed in individuals with TP53-related cancers (PMID: 10486318, 17606709, 18685109, 20455025, 20522432, 21601526, 23175693, 23894400, 24764719, 26014290). It has also been observed to segregate with disease in related individuals. This variant is also known as c.12407G>A. ClinVar contains an entry for this variant (Variation ID: 141963). 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: 10229196, 12826609, 21343334, 25584008). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000255654 SCV000322153 pathogenic not provided 2023-04-12 criteria provided, single submitter clinical testing Observed in a few individuals not meeting classic Li-Fraumeni syndrome criteria but several with adrenocortical carcinoma (ACC), leading some authors to suggest this variant might cause reduced penetrance or later onset of tumors other than ACC similar to the TP53 Arg337His Brazilian founder variant (Robertson 2010, Ceelen 2011, Bougeard 2015); Published functional studies demonstrate partial to non-functional transactivation, intermediate levels of growth suppression and colony reduction (Smith 1999, Campomenosi 2001, Kato 2003, Monti 2011, Wasserman 2015, Kotler 2018, Giacomelli 2018, IARC); 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: 20308654, 14559903, 9738975, 21665242, 24590827, 22768918, 27343442, 24764719, 12826609, 26786923, 16494995, 17311302, 21761402, 23894400, 27619989, 18511570, 25584008, 11896595, 9115587, 9399658, 10519380, 12917626, 20522432, 20455025, 21343334, 21464421, 20593220, 21552135, 21601526, 23117049, 25773284, 24829203, 24868540, 24198462, 19671995, 26014290, 23175693, 10486318, 10229196, 28369373, 27501770, 27157322, 28408749, 18685109, 29085664, 28749946, 28466600, 28922847, 28597078, 29058986, 27844328, 25234657, 22170717, 21339461, 10864200, 28349240, 27328919, 25741868, 29755662, 29707145, 28887601, 28724667, 17606709, 11429705, 17308077, 29300620, 29979965, 31016814, 30840781, 31081129, 30092803, 30224644, 31494577, 31447099, 30720243, 31105275, 32427313, 32817165, 33372952, 34240179, 31721094, 33858029, 34308104, 34863587, 35974385, 15510160, 35418818)
Color Diagnostics, LLC DBA Color Health RCV000130708 SCV000537627 pathogenic Hereditary cancer-predisposing syndrome 2023-05-11 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 158 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein exhibits a significantly decreased transactivation activity (PMID: 10229196, 12826609, 21343334, 25584008, 28472496) and cell growth control activity (PMID: 10229196, 25584008, 29979965, 30224644). This variant has been reported in individuals affected with classic Li-Fraumeni syndrome (PMID: 18685109, 20522432, 21552135, 31081129, 34540492) and in individuals fulfilling the Chompret criteria for Li-Fraumeni syndrome (PMID: 10486318, 10864200, 17308077, 20455025, 21601526, 23175693, 23894400, 24764719, 25584008, 26014290, 27501770, 28472496, 30092803; Lu et al 2021, DOI: 10.1158/1538-7445.AM2021-810). Ages of onset ranged from childhood to adulthood, and several carriers were reported to be unaffected (PMID: 17308077, 21601526, 27501770, 28472496). This variant has been shown to segregate with disease in multiple families (PMID: 17308077, 21464421, 24764719, 34540492; IARC database), including a family with a proband affected with malignant peritoneal mesothelioma and her five first-degree relatives affected with Li-Fraumeni syndrome spectrum tumors (PMID: 21464421). This variant has been identified in 1/251268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Multiple different missense substitutions occurring at the same codon (p.Arg158Gly, p.Arg158Leu and p.Arg158Pro) have been observed in individuals affected with Li-Fraumeni syndrome and have been shown to disrupt TP53 function (ClinVar variation ID: 856171, 528248, 246118). This indicates arginine at this position is a functionally and clinically important residue. Based on the available evidence, this variant is classified as Pathogenic.
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, Mass General Brigham 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 2022-10-06 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 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 4e-06 in 251268 control chromosomes.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). Ten 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
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000255654 SCV002011371 pathogenic not provided 2021-11-03 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000496787 SCV002579128 pathogenic Li-Fraumeni syndrome 1 2022-09-06 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000130708 SCV002582392 likely pathogenic Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000496787 SCV002583053 likely pathogenic Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV000496787 SCV004015237 pathogenic Li-Fraumeni syndrome 1 2023-07-07 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 158 of the TP53 protein (p.Arg158His). This variant is not observed at significant frequency in large population cohorts (gnomAD) . This missense change has been observed in individuals with TP53-related cancers (PMID: 10486318, 17606709, 18685109, 20455025, 20522432, 21601526, 23175693, 23894400, 24764719, 26014290). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 141963). In silico analysis supports that this missense variant has a deleterious effect on protein structure/function. Also,advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, aminoacid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TP53 protein function. (PMID: 10229196, 12826609, 21343334, 25584008). For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000227859 SCV004046280 pathogenic Li-Fraumeni syndrome criteria provided, single submitter clinical testing This variant has been previously reported as a heterozygous change in patients with TP53-related cancers and Li-Fraumeni syndrome (PMID: 10486318, 23894400, 20455025, 24764719, 26014290, 23175693, 20522432, 17606709, 21601526, 18685109). Experimental studies have shown that this variant affects TP53 function (PMID: 10229196, 12826609, 25584008, 21343334). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0003% (1/251268) and thus is presumed to be rare. The c.473G>A (p.Arg158His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.473G>A (p.Arg158His) variant is classified as Pathogenic.
Baylor Genetics RCV003461996 SCV004206277 pathogenic Adrenocortical carcinoma, hereditary 2023-05-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255654 SCV004221359 pathogenic not provided 2022-01-21 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.000099 (1/10070 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Li Fraumeni Syndrome (LFS), breast cancer, acute myeloid leukemia, and Li Fraumeni Syndrome associated cancers (PMIDs: 33372952 (2020), 32427313 (2020), 31105275 (2019), 31081129 (2019), 27501770 (2016), 26014290 (2015), 23894400 (2013), 22186996 (2012), 21761402 (2012), 21601526 (2011), 21464421 (2011)). Published functional studies have reported that this variant results in a damaging affect on TP53 protein function (PMIDs: 28472496 (2017), 25584008 (2015), 20522432 (2010), IARC TP53 https://p53.iarc.fr/). Based on the available information, this variant is classified as pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003492603 SCV004239786 likely pathogenic Breast and/or ovarian cancer 2022-12-23 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 2020-09-01 no assertion criteria provided provider interpretation
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000255654 SCV001740428 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute RCV000255654 SCV001906425 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000255654 SCV001958234 likely pathogenic not provided no assertion criteria provided clinical testing

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