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

gnomAD frequency: 0.00001  dbSNP: rs587782144

Total submissions: 27

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.
Labcorp Genetics (formerly Invitae), Labcorp	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	2024-06-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate partial to non-functional transactivation, intermediate levels of growth suppression and colony reduction (PMID: 29979965, 11429705, 12826609, 21343334, 25584008, 10229196); 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 (PMID: 26014290, 20455025, 21464421); 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: 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, 35418818, 34273903, 35988656, 36495689, 37461096, 12909720, 28472496, 15510160, 37179382)
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
Myriad Genetics, Inc.	RCV000496787	SCV004933726	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-14	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21464421, 17308077]. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 10229196].
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV000130708	SCV005407757	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-18	criteria provided, single submitter	clinical testing	c.473G>A, located in exon 5 of the TP53 gene, is predicted to result in the substitution of Arginine by Histidine at codon 158, p.(Arg158His). It is not present in the population database gnomAD v2.1.1, non-cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C25; BayesDel: 0.53) (PP3). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). At least, this variant has been reported in 8 individuals affected with a TP53-related phenotype, which awards 4.5 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID: 10486318, 17308077, 20522432, 23175693, 24764719) (PS4). The variant co-segregates in affected individuals (3 meiosis, 2 families) (PMID: 17308077, 24764719). It has been reported in ClinVar (15x as pathogenic, 4x as likely pathogenic) and CancerHotspots (36 somatic observations, PM1). Based on the currently available information, c.473G>A is classified as a pathogenic variant according to ClinGen-TP53 Guidelines version 1.4.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796030	SCV005416009	pathogenic	Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Choroid plexus papilloma; Basal cell carcinoma, susceptibility to, 7; Familial pancreatic carcinoma; Hepatocellular carcinoma; Colorectal cancer; Bone marrow failure syndrome 5		criteria provided, single submitter	clinical testing	PM2_Supporting+PS3_Moderate+PM5+PS4+PP1_Moderate
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