Submissions for variant NM_000546.6(TP53):c.848G>A (p.Arg283His)

gnomAD frequency: 0.00001  dbSNP: rs371409680

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131388	SCV000186364	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-11	criteria provided, single submitter	clinical testing	The p.R283H variant (also known as c.848G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 848. The arginine at codon 283 is replaced by histidine, an amino acid with highly similar properties. This alteration was identified in a 41 year-old male with astrocytoma (Fulci G et al. Cancer Res. 2002 May;62:2897-905). This alteration has been identified in one family with a history consistent with Li-Fraumeni-like syndrome; however, this alteration has also been detected numerous times in our laboratory in individuals with a personal and family history inconsistent with a diagnosis of Li Fraumeni syndrome (Ambry internal data). Transactivation studies conducted in yeast and mammalian cells have shown variable results, with the altered protein able to activate some, but not all, downstream targets (Fulci G et al. Cancer Res. 2002 May;62:2897-905; Campomenosi P et al. Oncogene. 2001 Jun;20:3573-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9; Dearth LR et al. Carcinogenesis. 2007 Feb;28:289-98; Crook T et al. Oncogene. 1998 Mar;16:1429-41; IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul;100:8424-9). This variant also has conflicting reports of intracellular localization, with one group showing nuclear localization in yeast (Dearth LR et al. Carcinogenesis. 2007 Feb;28:289-98), and another showing nuclear exclusion in a human lymphoma cell line (Crook T et al. Oncogene. 1998 Mar;16:1429-41). However, this alteration has been shown to be proficient at growth suppression in multiple mammalian cell lines (Crook T et al. Oncogene. 1998 Mar;16:1429-41; Fulci G et al. Cancer Res. 2002 May;62:2897-905; Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear, and we cannot rule out the possibility that it is a low penetrance risk allele.
CSER _CC_NCGL, University of Washington	RCV000148904	SCV000190650	uncertain significance	Astrocytoma	2016-06-16	criteria provided, single submitter	research	Identified by sequencing as part of the NHLBI Sequencing Project (ESP; no phenotype data). Reported in a patient with astroctyoma (PMID 12019170). Identified in a 14 year old with adrenocortical carcinoma inherited from an unaffected father and in a 32 year old woman with a history of cardiac paraganglioma and maternal family history of breast cancer (personal communication with Chimene Kesserwan and Arielle Yorczyk-Swanholm).
GeneDx	RCV000213060	SCV000211762	uncertain significance	not provided	2024-03-15	criteria provided, single submitter	clinical testing	Published functional studies are conflicting: this variant is reported to have non-functional transactivation; however, p53 response elements other than the BAX reporter have been normal or partially present, apoptotic activity was not impacted, and colony formation and growth suppression assays were similar to wild type (PMID: 9525742, 9627118, 9546439, 10753186, 11429705, 11238924, 11429700, 12019170, 11896595, 12909720, 16861262, 21343334, 29979965, 30224644, 12826609); Identified in individuals with breast, brain, or other cancers, with none to date reported as meeting Li-Fraumeni diagnostic criteria (PMID: 10557074, 30128536, 35451682); 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: 25637381, 12909720, 11429700, 29979965, 17606709, 21343334, 30577483, 28861920, 30128536, 29922827, 30851333, 12019170, 9525742, 21674059, 11238924, 10753186, 11429705, 11896595, 16861262, 9546439, 26681312, 10229196, 28915717, 29301828, 28418444, 28218421, 9627118, 30352134, 30720243, 30840781, 31016814, 33257846, 30224644, 17311302, 32164171, 32722340, 32966936, 31105275, 31620276, 16000567, 12917626, 9572492, 35451682, 35490794, 10557074, 15173255, 24729566, 25460562, 35033608, 36353970, 18628487, 26743472, 15580553, 11715068, 11358831, Fu2022, 12826609, 15510160, 36243179)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457935	SCV000545319	uncertain significance	Li-Fraumeni syndrome	2024-02-01	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 283 of the TP53 protein (p.Arg283His). This variant is present in population databases (rs371409680, gnomAD 0.01%). This missense change has been observed in individual(s) with astrocytoma and glioblastoma (PMID: 10557074, 12019170). ClinVar contains an entry for this variant (Variation ID: 142324). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 9525742, 9546439, 9627118, 11429705, 12019170, 12826609, 16861262, 17311302, 21343334, 29979965, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genetic Services Laboratory, University of Chicago	RCV001815237	SCV000597520	uncertain significance	not specified	2020-05-19	criteria provided, single submitter	clinical testing	DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.848G>A, in exon 8 that results in an amino acid change, p.Arg283His. This sequence change has been reported in the gnomAD databases with an overall frequency of 0.004% and 0.01% in the South Asian population (dbSNP rs371409680). The p.Arg283His has been described in an individual with TP53-related astrocytoma and glioblastoma (PMID: 12019170) and an individual with breast cancer (PMID: 26681312). Functional studies have demonstrated that this variant may affect TP53 transactivation activity to varying degrees, with some demonstrating retention of near-wild-type protein function (PMID: 21343334, 12019170, 12826609, 9627118, 16861262, 9546439, 11429705). One study revealed that this variant leads to mislocalization of the TP53 protein, but retained some growth suppressive and apoptotic activity (PMID: 9525742). The p.Arg283His change affects a moderately conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Arg283His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). Due to the conflicting functional studies and the presence of this variant in the population databases, the clinical significance of the p.Arg283His change remains unknown at this time.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000213060	SCV000602281	uncertain significance	not provided	2023-12-07	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 26681312 (2015)), follicular lymphoma (PMID: 18628487 (2008)), astrocytoma (PMID: 10557074 (1999)), as well as in unaffected individuals (PMIDs: 32906206 (2020), 33471991 (2021)). Published functional studies report that the variant retained normal transactivation of most p53 target promoters except for the BAX promoter and had no impact on apoptotic activity or cell growth suppression (PMIDs: 29979965 (2018), 21343334 (2011), 16861262 (2007), 16000567 (2005), 12019170 (2002), 10229196 (1999), 9627118 (1998), 9546439 (1998), 9525742 (1998)). The frequency of this variant in the general population, 0.00013 (4/30614 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507738	SCV000605420	uncertain significance	Li-Fraumeni syndrome 1	2020-02-06	criteria provided, single submitter	clinical testing	The TP53 c.848G>A; p.Arg283His variant (rs371409680), is reported in the literature in individuals affected with an astrocytoma or a glioblastoma (Fulci 2002, Ishii 1999) and in an individual with breast cancer (Susswein 2016). This variant is reported as likely pathogenic/uncertain significance by multiple laboratories in ClinVar (Variation ID: 142324), and is found in the general population with an overall allele frequency of 0.004% (10/ 251,452 alleles) in the Genome Aggregation Database. The arginine at codon 283 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show variable results, although many show decreased transactivation and a moderate dominant-negative effect (see link TP53MutLoad database, Campomenosi 2001, Crook 1998, Di Como 1998, Flaman 1998, Fulci 2002). Additionally, recent analyses of Genome Aggregation Database frequency compared to affected individuals do not reach a consensus as to the clinical significance (Evans 2019, Fortuno 2019, Soussi 2019). Therefore, due to conflicting results, the clinical significance of this variant is uncertain.
Color Diagnostics, LLC DBA Color Health	RCV000131388	SCV000903096	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 283 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). Experimental functional studies assessing transcriptional transactivation activity have demonstrated partial impact to normal function (PMID: 9525742, 9546439, 9627118, 11429700, 11429705, 12826609, 16861262, 17311302, 21343334). However, studies of human cell proliferation and growth suppression showed no loss of TP53 function (PMID: 29979965, 30224644). This variant has been reported in individuals affected with breast cancer and astrocytoma in the literature (PMID: 10557074, 12019170, 26681312; DOI: 10.21203/rs.3.rs-1200021/v2). This variant has been identified in 10/251452 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000507738	SCV001950095	uncertain significance	Li-Fraumeni syndrome 1	2021-07-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415959	SCV004107241	uncertain significance	TP53-related disorder	2023-07-18	criteria provided, single submitter	clinical testing	The TP53 c.848G>A variant is predicted to result in the amino acid substitution p.Arg283His. This variant was reported in individuals with astrocytoma, glioblastoma, or breast cancer (Fulchi et al. 2002. PubMed ID: 12019170; Table S1, Susswein et al. 2016. PubMed ID: 26681312; Table S4, Rana et al. 2019. PubMed ID: 31105275). However, this variant was also documented in individuals unselected for cancer testing (Table S1, de Andrade et al. 2017. PubMed ID: 28861920; Evans et al. 2019. PubMed ID: 31016814). Functional studies in different laboratories showed variable and even contradictory results regarding the transactivation activity and subcellular localization (Crook et al. 1998. PubMed ID: 9525742; Dearth et al. 2006. PubMed ID: 16861262; Table S1, Monti et al. 2007. PubMed ID: 17606709; Tables S1 and S3, Monti et al. 2011. PubMed ID: 21343334). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7577090-C-T) and is interpreted as a variant of uncertain significance by most of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142324/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003467172	SCV004206220	uncertain significance	Adrenocortical carcinoma, hereditary	2023-10-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000457935	SCV004823759	uncertain significance	Li-Fraumeni syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 283 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies assessing transcriptional transactivation activity have demonstrated partial impact to normal function (PMID: 9525742, 9546439, 9627118, 11429700, 11429705, 12826609, 16861262, 17311302, 21343334). However, studies of human cell proliferation and growth suppression showed no loss of TP53 function (PMID: 29979965, 30224644). This variant has been reported in individuals affected with breast cancer and astrocytoma in the literature (PMID: 10557074, 12019170, 26681312; DOI: 10.21203/rs.3.rs-1200021/v2). This variant has been identified in 10/251452 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.