ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.743G>A (p.Arg248Gln)

gnomAD frequency: 0.00002  dbSNP: rs11540652
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Total submissions: 66
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV000197114 SCV001142549 pathogenic Li-Fraumeni syndrome 2019-08-28 reviewed by expert panel curation This variant is within a codon that is an established hotspot in the TP53 gene (PM1; PMID: 2046748). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has been reported in at least 3 probands meeting classic Li-Fraumeni syndrome and 2 probands meeting Chompret criteria (PS4; PMID: 1565143, 9242456, 15381368, 7887414). There is a de novo observation of a proband with adrenocortical carcinoma with parental confirmation (PS2; PMID: 15381368). In summary, TP53 c.743G>A; p.Arg248Gln meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM1, PP3, PS3, PS4, PS2.
GeneDx RCV000235221 SCV000149645 pathogenic not provided 2021-12-03 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression and apoptotic activities, dominant-negative effect (Lomax et al., 1998; Kato et al., 2003; Dearth et al., 2007; Monti et al., 2011; Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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, 24573247, 23334668, 21305319, 9704930, 15004724, 7718482, 12124823, 15541116, 9738975, 16322298, 8252037, 17606709, 22851211, 2263646, 26787237, 29300620, 29489754, 20128691, 21343334, 22110706, 24651015, 21761402, 19367569, 18048389, 8080050, 16861262, 18555592, 10557074, 10567903, 10914716, 16142349, 8707423, 10519380, 12917626, 10753186, 8062826, 7682763, 1915267, 7478555, 16959974, 12509970, 26703669, 28154273, 27153395, 26822237, 28724667, 28369373, 28125075, 29979965, 29478780, 28861920, 23538418, 30076369, 29752822, 26556299, 28975465, 29753700, 30092803, 30720243, 30093976, 30840781, 30553995, 31159747, 31081129, 19012332, 1565143, 25612911, 21601526, 7887414, 24810334, 27683180, 30709875, 15510160, 21552135, 1458490, 16778209, 10754498, 12826609, 31105275, 31447099, 32029870, 33818021, 33300245, 31851316, 32658383, 30982232, 33245408, 30875412, 32427313, 33674644)
Ambry Genetics RCV000115736 SCV000185472 pathogenic Hereditary cancer-predisposing syndrome 2021-10-28 criteria provided, single submitter clinical testing The p.R248Q (also known as c.743G>A) pathogenic mutation is located in coding exon 6 of the TP53 gene. This alteration results from a G to A substitution at nucleotide position 743. The arginine at codon 248 is replaced by glutamine, an amino acid with some similar properties. This alteration has been described as a de novo mutation in a woman with multiple primary osteosarcomas and bilateral breast cancer and her daughter with childhood-onset sarcoma (Toguchida J et al. N Engl J Med. 1992 May 14;326(20):1301-8). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). 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). This alteration has been shown to be involved in DNA binding through crystal structure analysis (Martin AC et al. Hum. Mutat. 2002 Feb; 19(2):149-64). To date, this alteration has been detected in numerous LFS families and other pathogenic missense mutations at codon 248 have been reported (Petitjean A et al. IARC TP53 database [version R15, November 2010]. Hum Mutat. 2007 Jun;28(6):622-9; Stenson et al. The Human Gene Mutation Database (HGMD®): 2003 Update. Hum Mutat. 2003;21:577-581). Based on the available evidence, this alteration is classified as a pathogenic mutation.
Eurofins Ntd Llc (ga) RCV000235221 SCV000232078 pathogenic not provided 2014-06-09 criteria provided, single submitter clinical testing
Invitae RCV000197114 SCV000253851 pathogenic Li-Fraumeni syndrome 2024-01-25 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 248 of the TP53 protein (p.Arg248Gln). This variant is present in population databases (rs11540652, gnomAD 0.006%). This missense change has been observed in individual(s) with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 1565143, 7887414, 17606709, 21305319, 21601526). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12356). 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: 17606709, 20128691, 21343334). This variant disrupts the p.Arg248 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8062826, 9546439, 12826609, 15722483; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington RCV000115736 SCV000266133 likely pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115736 SCV000686766 pathogenic Hereditary cancer-predisposing syndrome 2022-11-01 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 248 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 the mutant protein to be non-functional in DNA binding and transactivation assays (PMID: 9704930, 12826609, 20128691, 21343334, 23538418, 28369373), and defective in cell growth inhibition, apoptosis, and proliferation assays (PMID: 9704930, 21187651, 29979965, 30224644). This variant has been reported in numerous individuals affected with Li-Fraumeni syndrome (PMID: 1565143, 1683921, 7887414, 9242456, 10797439, 11139324, 11479205, 17606709, 18511570, 19556618, 21305319, 21552135, 21601526, 25612911, 26822237, 27683180 ) and breast cancer (PMID: 11139324, 16489069, 21761402, 30287823, 32000721, 33471991). It also has been observed de novo in Li Fraumeni patients with paternity confirmed (PMID: 15381368, 24810334). This variant has been identified in 3/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Counsyl RCV000013150 SCV000785422 likely pathogenic Li-Fraumeni syndrome 1 2017-07-27 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115736 SCV000821785 pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This sequence change replaces Arginine with Glutamine at codon 248 of the TP53 protein. The arginine residue is highly conserved among species and is located in a functional domain of the protein. There is a small physiochemical difference between arginine and glutamine (Grantham Score 43).This variant is present in population databases at a very low frequency (rs11540652, ExAC 0.02%) and has been reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 1565143, 17606709, 21601526).Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein. Moreover, experimental studies have shown that this missense change severely affects the functional activity of the p53 protein. This variant is classified as a severe deficiency allele with possible dominant-negative inhibitory effects (PMID: 21343334, 17606709, 20128691). The mutation database Clinvar contains entries for this variant (Variation ID:12356).
Mendelics RCV000197114 SCV000839112 pathogenic Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000763417 SCV000894154 pathogenic Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Carcinoma of colon; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma 2018-10-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235221 SCV001134877 pathogenic not provided 2023-05-09 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.000026 (3/113756 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in multiple Li-Fraumeni syndrome families (PMID: 21305319 (2011), 21601526 (2011), 17606709 (2007), 7887414 (1995), 1565143 (1992), 9242456 (1997)), as well as in individuals with breast cancer (PMID: 30287823 (2018), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/TP53)). Additionally, this variant has been shown to affect DNA binding and transactivation activities (PMID: 21343334 (2011), 20128691 (2010), 17606709 (2007)), as well as shown to have a dominant negative effect (PMID: 30224644 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000197114 SCV001363225 pathogenic Li-Fraumeni syndrome 2019-09-20 criteria provided, single submitter clinical testing Variant summary: TP53 c.743G>A (p.Arg248Gln) results in a conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251474 control chromosomes (gnomAD). c.743G>A has been reported in the literature in multiple individuals/families affected with Li-Fraumeni or Li-Fraumeni-like syndromes (e.g. Haque_2018, Rapakko_2001, Vahteristo_2001, Villani_2011) while, it was also reported in a LFS patient with a suggested de novo occurrence (Bendig_2004). These data indicate that the variant is very likely to be associated with disease. Functional studies demonstrate that the R248Q substitution impairs the DNA binding capability of TP53 essential for its tumor suppressor function (Merabet_2010), and the variant exhibited less than 25% of wild-type transcriptional transactivation activity. Additional studies have classified this variant as a severe deficiency allele with a dominant negative effect (Monti_2011, Zerdoumi_2017). Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital RCV000235221 SCV001449921 likely pathogenic not provided 2018-06-25 criteria provided, single submitter clinical testing
Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo RCV001270275 SCV001450492 pathogenic Familial cancer of breast criteria provided, single submitter case-control
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000013150 SCV002525970 pathogenic Li-Fraumeni syndrome 1 2022-02-17 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000235221 SCV002585617 pathogenic not provided 2023-08-01 criteria provided, single submitter clinical testing TP53: PP1:Strong, PM1, PM2, PM5, PS3:Moderate, PS4:Supporting
3billion RCV000013150 SCV003841287 pathogenic Li-Fraumeni syndrome 1 2023-02-23 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12826609, 30224644). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012356 / PMID: 1565143). The variant has been previously reported as de novo in a similarly affected individual (PMID: 15381368). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 15381368, 1565143, 7887414, 9242456). Different missense changes at the same codon (p.Arg248Gly, p.Arg248Leu, p.Arg248Pro, p.Arg248Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012347, VCV000230253, VCV000237954, VCV000376652, VCV000437017 / PMID: 11180592, 1978757, 28152038, 31105275). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Myriad Genetics, Inc. RCV000013150 SCV004017915 pathogenic Li-Fraumeni syndrome 1 2023-04-12 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15381368, 1565143, 8118819, 7887414]. Functional studies indicate this variant impacts protein function [PMID: 8023157, 10411893, 23538418, 21445056].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000235221 SCV004026687 pathogenic not provided 2023-08-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV003466852 SCV004206252 pathogenic Adrenocortical carcinoma, hereditary 2023-07-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000197114 SCV004847499 pathogenic Li-Fraumeni syndrome 2011-11-23 criteria provided, single submitter clinical testing The Arg248Gln is a recurrent variant in TP53 which has been reported in more than 10 individuals with Li-Fraumeni syndrome (LFS; Santibanez-Koref 1991, Toguchida 1992, Frebourg 1995, Marsciari 2011, Villani 2011, Wu 2011, IARC TP53 Database). This variant shows moderate segration with disease among affected family members (>5 meiosis) and was absent from over 400 control choromosomes (Toguchida, 1992). In addition this variant is predicited to create a new splice site which could disrupt protein function or lead to absent protein (Kouidou 2009). Based on this information, this variant is highly likely to be pathogenic.
OMIM RCV000013150 SCV000033397 pathogenic Li-Fraumeni syndrome 1 2000-05-15 no assertion criteria provided literature only
Pathway Genomics RCV000013150 SCV000190000 pathogenic Li-Fraumeni syndrome 1 2014-07-24 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148913 SCV000190659 pathogenic Sarcoma 2014-06-01 no assertion criteria provided research
Database of Curated Mutations (DoCM) RCV000445244 SCV000504693 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426606 SCV000504694 likely pathogenic Neoplasm 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437291 SCV000504695 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419135 SCV000504696 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426359 SCV000504697 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437935 SCV000504698 likely pathogenic Myelodysplastic syndrome 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420727 SCV000504699 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430513 SCV000504700 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441226 SCV000504701 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417916 SCV000504702 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428591 SCV000504703 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438410 SCV000504704 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421194 SCV000504705 likely pathogenic Ovarian serous cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432778 SCV000504706 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439963 SCV000504707 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421893 SCV000504708 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432587 SCV000504709 likely pathogenic Uterine carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445235 SCV000504710 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426233 SCV000504711 likely pathogenic Prostate adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433424 SCV000504712 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444656 SCV000504713 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427709 SCV000504714 likely pathogenic Medulloblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437518 SCV000504715 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420303 SCV000504716 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424869 SCV000504717 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435533 SCV000504718 likely pathogenic B-cell chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Donald Williams Parsons Laboratory, Baylor College of Medicine RCV000013150 SCV000599966 pathogenic Li-Fraumeni syndrome 1 2012-12-27 no assertion criteria provided research This variant has been previously reported as disease-causing and was found once in our study maternally inherited in a 2-year-old female with neuroblastoma, in a family meeting criteria for Li-Fraumeni (history of early breast, brain tumors, rhabdomyosarcoma).
Mayo Clinic Laboratories, Mayo Clinic RCV000235221 SCV000692073 pathogenic not provided no assertion criteria provided clinical testing
Genome Sciences Centre, British Columbia Cancer Agency RCV001789749 SCV000693734 pathogenic Colorectal cancer 2016-04-12 no assertion criteria provided research
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000785344 SCV000923912 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center RCV000790860 SCV000930032 likely pathogenic Lymphoma 2019-07-25 no assertion criteria provided clinical testing
Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center RCV000424869 SCV001132099 likely pathogenic Multiple myeloma 2019-08-31 no assertion criteria provided clinical testing
Institute of Medical Sciences, Banaras Hindu University RCV001255671 SCV001432236 pathogenic Lip and oral cavity carcinoma 2019-04-30 no assertion criteria provided research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001257519 SCV001434345 pathogenic Rhabdomyosarcoma 2020-09-01 no assertion criteria provided provider interpretation
University Health Network, Princess Margaret Cancer Centre RCV001527465 SCV001738480 pathogenic Ductal carcinoma in situ 2021-03-19 no assertion criteria provided clinical testing
University Health Network, Princess Margaret Cancer Centre RCV001270275 SCV001738502 pathogenic Familial cancer of breast 2021-03-19 no assertion criteria provided clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences RCV001554245 SCV001774820 pathogenic Breast carcinoma 2021-08-08 no assertion criteria provided clinical testing
BRCAlab, Lund University RCV000115736 SCV002589035 pathogenic Hereditary cancer-predisposing syndrome 2022-08-26 no assertion criteria provided clinical testing
Laboratory for Genotyping Development, RIKEN RCV003162244 SCV002758165 pathogenic Gastric cancer 2021-07-01 no assertion criteria provided research
Laboratory of Urology, Hospital Clinic de Barcelona RCV003332079 SCV004040602 pathogenic Malignant tumor of urinary bladder no assertion criteria provided research
Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University RCV003996090 SCV004046836 likely pathogenic Adrenal cortex carcinoma no assertion criteria provided clinical testing

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