Submissions for variant NM_000546.6(TP53):c.742C>T (p.Arg248Trp)

dbSNP: rs121912651

Total submissions: 58

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000168242	SCV001142555	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: 20182602). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). 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 with classic Li-Fraumeni syndrome criteria and 2 probands meeting Chrompret criteria (PS4; PMID: 8425176, 20522432, 23667202, 9242456). This variant was found to co-segregate with disease in multiple affected family members, with >7 meioses observed across at least two families (PP1_Strong; PMID: 1978757, 9825943). There is a de novo observation of a proband with a rhabdomyosarcoma with parental confirmation (PS2; PMID: 10089074). In summary, TP53 c.742C>T; p.Arg248Trp 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_Moderate, PS3, PS4, PP1_Strong, PS2.
GeneDx	RCV000213057	SCV000149644	pathogenic	not provided	2022-05-11	criteria provided, single submitter	clinical testing	Observed in several individuals and families meeting Li-Fraumeni or Li-Fraumeni like criteria (Malkin et al., 1990, Birch et al., 1994, Hwang et al., 2003, Monti et al., 2007, Rossbach et al., 2008, Serra et al., 2013, Villani et al., 2016); Published functional studies demonstrate a damaging effect: non-functional transactivation, dominant-negative effect, loss of growth suppression activity (Kato et al., 2003, Willis et al., 2004, Grochova et al., 2008, Monti et al., 2011, Kotler et al., 2018); Not observed at a 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: 8118819, 27501770, 26215675, 1978757, 12209590, 12610779, 27374712, 24603336, 16959974, 28387325, 28527674, 29979965, 25525159, 19378321, 30076369, 29324801, 20128691, 15280671, 17606709, 17724467, 14743206, 1565144, 25925845, 24651015, 26787237, 27714481, 22265402, 23950206, 9764816, 17427234, 27323394, 26223322, 25958320, 26703669, 23172776, 24573247, 21343334, 26681312, 28831167, 29025599, 28369373, 29077933, 28915717, 28356770, 28735817, 28624650, 29489754, 29730572, 30042819, 11051239, 28472496, 28724667, 29752822, 30092803, 29753700, 29961768, 30720243, 21686767, 31016814, 30840781, 30137042, 31081129, 15510160, 12826609, 29625052, 31105275, 31447099, 31775759, 32930885, 33818021, 32475984, 33300245, 30755392, 32658383, 32817165, 33245408, 33087929)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000168242	SCV000204074	pathogenic	Li-Fraumeni syndrome	2020-01-10	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Ambry Genetics	RCV000115735	SCV000212766	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-10	criteria provided, single submitter	clinical testing	The p.R248W pathogenic mutation (also known as c.742C>T), located in coding exon 6 of the TP53 gene, results from a C to T substitution at nucleotide position 742. The arginine at codon 248 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in many individuals and families from various ethnicities affected with Li-Fraumeni syndrome-associated cancers (Malkin D et al. Science. 1990 Nov 30;250(4985):1233-8; Bang YJ et al. J. Korean Med. Sci. 1995 Jun;10:205-10; Alsner J et al. Clin Cancer Res. 2000 Oct;6(10):3923-31; Andrade RC et al. Pediatr Blood Cancer. 2013 Sep 13; Rieber J et al. Genes Chromosomes Cancer. 2009 Jul; 48(7):558-68; Arcand SL et al. BMC Med. Genet. 2015 Apr;16:24; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119). This mutation was also reported in an individual diagnosed with bilateral breast cancer at ages 29 and 34; in vitro studies showed significantly reduced induction levels of TP53 target genes in LFS lymphocytes that had been exposed to DNA damage resulting in greatly reduced cellular response to DNA damage (Zerdoumi Y et al. Hum Mutat. 2013 Mar;34(3):453-61). 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). In another study, a functional protein microarray indicated that TP53 polypeptide with p.R248W alteration exhibited less than 40% DNA binding activity compared to wild type protein (Malcikova J et al. Biol Chem. 2010 Feb-Mar;391(2-3):197-205). 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	RCV000168242	SCV000218912	pathogenic	Li-Fraumeni syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 248 of the TP53 protein (p.Arg248Trp). This variant is present in population databases (rs121912651, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome and breast cancer (PMID: 1978757, 23172776, 23950206, 24573247). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12347). 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: 12826609, 17606709, 20128691, 21343334, 23172776, 29979965, 30224644). 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: 17606709, 20128691). 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.
Counsyl	RCV000013140	SCV000488942	pathogenic	Li-Fraumeni syndrome 1	2016-07-25	criteria provided, single submitter	clinical testing
Mendelics	RCV000168242	SCV000839113	pathogenic	Li-Fraumeni syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV000735293	SCV000854446	pathogenic	Pectus excavatum; Acute myeloid leukemia; Short stature; Cognitive impairment; Webbed neck; Pancytopenia; Abnormality of the tongue		criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000213057	SCV001469327	pathogenic	not provided	2019-10-25	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. One de novo case with parental identity not confirmed.
Baylor Genetics	RCV000013140	SCV002030213	pathogenic	Li-Fraumeni syndrome 1	2021-02-09	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Color Diagnostics, LLC DBA Color Health	RCV000115735	SCV002053464	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-12	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan 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). This variant occurs at an established tumor hotspot in the TP53 protein (PMID: 20182602, 26619011). Functional studies have shown that this variant is defective for DNA binding and transcriptional transactivation of TP53 target genes, displays loss of function and dominant negative activity in human cell growth suppression assays and is non-functional in human cell proliferation assays (PMID: 12826609, 17417627, 20013323, 21343334, 23172776, 28369373, 29979965, 30224644). This variant has been reported in individuals affected with Li Fraumeni syndrome cancers (PMID: 1978757, 1631137, 8425176, 9598730, 17606709, 17427234, 20522432, 23172776, 23667202, 23950206, 27374712, 28369373). It has been shown that this variant segregates with disease in Li Fraumeni families (PMID: 1978757, 8527048, 9242456, 9825943) and has been observed to occur de novo (PMID: 10089074, 29025599). This variant has been identified in 1/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000013140	SCV002525951	pathogenic	Li-Fraumeni syndrome 1	2022-01-10	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000013140	SCV003807904	pathogenic	Li-Fraumeni syndrome 1	2022-04-01	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS2 strong, PS3 strong, PS4 strong, PM1 moderated, PM2 moderated, PP1 strong, PP3 supporting
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149569	SCV003837775	pathogenic	Breast and/or ovarian cancer	2021-09-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168242	SCV003844260	pathogenic	Li-Fraumeni syndrome	2023-02-27	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.742C>T (p.Arg248Trp) 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 251490 control chromosomes. c.742C>T has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome or other types of cancer. These data indicate that the variant is very likely to be associated with disease. At least two publication reports experimental evidence evaluating an impact on protein function and showed that this variant results in abrogation of Tp53 tumor suppressor activity (Fregourg_1992, Zerdoumi_2012). Twelve 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. Based on the evidence outlined above, the variant was classified as pathogenic.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000013140	SCV003932859	pathogenic	Li-Fraumeni syndrome 1	2023-06-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 248 of the TP53 protein (p.Arg248Trp). This variant is present in population databases (rs121912651, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome and breast cancer (PMID: 1978757, 23172776, 23950206, 24573247). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12347) with 52 entries, all of which classify this variant as pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 17606709, 20128691, 21343334, 23172776, 29979965, 30224644). 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: 17606709, 20128691). Therefore, this variant has been classified as Pathogenic. Pathogenic/likely pathogenic TP53 gene cause Li-Fraumeni syndrome.
Myriad Genetics, Inc.	RCV000013140	SCV004017842	pathogenic	Li-Fraumeni syndrome 1	2023-04-11	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: 10089074, 9242456, 20522432]. Functional studies indicate this variant impacts protein function [PMID: 17417627, 14743206, 9150393, 8062826].
Baylor Genetics	RCV003460463	SCV004206227	pathogenic	Adrenocortical carcinoma, hereditary	2023-09-27	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000013140	SCV004244617	pathogenic	Li-Fraumeni syndrome 1	2023-10-13	criteria provided, single submitter	clinical testing	PS3, PS4, PS2
All of Us Research Program, National Institutes of Health	RCV000168242	SCV004823768	pathogenic	Li-Fraumeni syndrome	2023-02-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan 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). This variant occurs at an established tumor hotspot in the TP53 protein (PMID: 20182602, 26619011). Functional studies have shown that this variant is defective for DNA binding and transcriptional transactivation of TP53 target genes, displays loss of function and dominant negative activity in human cell growth suppression assays and is non-functional in human cell proliferation assays (PMID: 12826609, 17417627, 20013323, 21343334, 23172776, 28369373, 29979965, 30224644). This variant has been reported in individuals affected with Li Fraumeni syndrome cancers (PMID: 1978757, 1631137, 8425176, 9598730, 17606709, 17427234, 20522432, 23172776, 23667202, 23950206, 27374712, 28369373). It has been shown that this variant segregates with disease in Li Fraumeni families (PMID: 1978757, 8527048, 9242456, 9825943) and has been observed to occur de novo (PMID: 10089074, 29025599). This variant has been identified in 1/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
OMIM	RCV000013140	SCV000033387	pathogenic	Li-Fraumeni syndrome 1	1992-07-15	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419032	SCV000504848	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429777	SCV000504849	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440422	SCV000504850	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423184	SCV000504851	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433905	SCV000504852	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441091	SCV000504853	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423804	SCV000504854	likely pathogenic	B-cell chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434504	SCV000504855	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442243	SCV000504856	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424415	SCV000504857	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431689	SCV000504858	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444845	SCV000504859	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425083	SCV000504860	likely pathogenic	Myelodysplastic syndrome	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435803	SCV000504861	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418495	SCV000504862	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425682	SCV000504863	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436398	SCV000504864	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419150	SCV000504865	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429884	SCV000504866	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440560	SCV000504867	likely pathogenic	Medulloblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419857	SCV000504868	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430543	SCV000504869	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441557	SCV000504870	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424308	SCV000504871	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431508	SCV000504872	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438698	SCV000504873	likely pathogenic	Neoplasm	2015-07-14	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785485	SCV000924057	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research
Institute of Medical Sciences, Banaras Hindu University	RCV001255674	SCV001432239	pathogenic	Lip and oral cavity carcinoma	2019-04-30	no assertion criteria provided	research
Michigan Center for Translational Pathology, University of Michigan	RCV001271100	SCV001451929	pathogenic	Choroid plexus carcinoma	2020-12-22	no assertion criteria provided	clinical testing
Institute of Medical Sciences, Banaras Hindu University	RCV001374442	SCV001571405	uncertain significance	Gallbladder cancer	2020-10-30	no assertion criteria provided	research
University Health Network, Princess Margaret Cancer Centre	RCV000785485	SCV001738478	pathogenic	Neoplasm of ovary	2021-03-19	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000213057	SCV001739798	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000213057	SCV001905841	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000213057	SCV001956921	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162243	SCV002758166	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003105772	SCV003762123	pathogenic	Congenital fibrosarcoma	2022-05-10	no assertion criteria provided	clinical testing
Wasik Lab, Fox Chase Cancer Center	RCV003318332	SCV004020303	pathogenic	Malignant lymphoma, large B-cell, diffuse	2023-07-25	no assertion criteria provided	clinical testing	This variant was observed in a patient with DLBCL that presented in leukemic form, best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. TP53 tumor suppressor dysregulation is associated with partial or no response to CHOP-based chemotherapy (Young et al. 2007; Xu-Monette et al. 2012). TP53 mutations frequently involve the DNA binding domain, exons 5-8, impairing TP53 mediated transcriptional transactivation (Miao et al. 2019). TP53 R248W was detected in this tumor at presentation and recurrence, and is predicted to cause structural defects in the region responsible for DNA binding. Genomic DNA copy number assays indicated the normal TP53 allele was lost at relapse. TP53 mutation is uncommon in the MYD88 cluster of DLBCL but when present, it confers an extremely poor prognosis (Lacy et al. 2020).