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

gnomAD frequency: 0.00002  dbSNP: rs11540652

Total submissions: 66

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