ClinVar Miner

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

dbSNP: rs121912651
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Total submissions: 58
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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).

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