ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.742C>T (p.Arg248Trp) (rs121912651)

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Total submissions: 44
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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 2018-07-02 criteria provided, single submitter clinical testing This variant is denoted TP53 c.742C>T at the cDNA level, p.Arg248Trp (R248W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has been observed in several individuals and families meeting Li-Fraumeni or Li-Fraumeni like criteria (Malkin 1990, Hwang 2003, Birch 1994, Monti 2007, Rossbach 2008, Serra 2013, Villani 2016). Functional assays have consistently found that TP53 Arg248Trp significantly impacts transcriptional activation of typical p53 targets and causes a dominant-negative effect (Willis 2004, Grochova 2008, Monti 2011). Additionally, this variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Arg248Trp is considered a hot spot" mutant and is one of the most common somatic variants in human cancer (Brachmann 2004, Willis 2004, Xu 2014). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). TP53 Arg248Trp is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic."
Laboratory for Molecular Medicine, Partners HealthCare 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 2019-05-03 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 has also been reported in 10 unrelated, affected families and has been described as a severe deficiency allele with only 1% residual transcriptional function when compared to wild type (Monti P et al. Clin Cancer Res. 2007 Jul 1;13(13):3789-95; Monti P et al. Mol Cancer Res. 2011 Mar;9(3):271-9). This alteration is in the DNA binding domain of the TP53 protein and 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). In one 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 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). Additional functional studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000168242 SCV000218912 pathogenic Li-Fraumeni syndrome 2020-09-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 248 of the TP53 protein (p.Arg248Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs121912651, ExAC 0.001%). This variant has been reported in the literature as one of the most commonly identified variants in individuals with Li-Fraumeni syndrome. It is also associated with a high incidence of breast cancer (PMID: 24573247, 23172776, 23950206, 1978757). ClinVar contains an entry for this variant (Variation ID: 12347) Experimental studies have shown that this missense change severely disrupts essential activities of the TP53 protein (PMID: 17606709, 20128691, 21343334, 23172776, 12826609). Another missense substitution at this codon (p.Arg248Gln) has also been determined to be deleterious (PMID: 17606709, 20128691), confirming that the Arg248 residue is important for TP53 protein function. 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
CHLA 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.
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 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 Adenocarcinoma of prostate 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 Adenocarcinoma of stomach 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 Center Cologne,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
Human Genetics - Radboudumc,Radboudumc RCV000213057 SCV001956921 pathogenic not provided no assertion criteria provided clinical testing

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