ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.997C>T (p.Arg333Cys) (rs769934890)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV001294069 SCV001737916 likely benign Li-Fraumeni syndrome 1 2021-04-19 reviewed by expert panel curation This variant has a BayesDel score >0.16 and Align GVGD (Zebrafish) is Class 25 or higher (PP3). This variant has been observed in 3 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributors). Transactivation assays show [retained/supertransactivation] function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). In this case, a single supporting evidence code (PP3) should not be considered conflicting evidence as variant otherwise meets criteria for Likely Benign classification. In summary, TP53 c.997C>T (p.Arg333Cys) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PP3, BS2_Supporting, BS3.
Ambry Genetics RCV000164055 SCV000214662 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-28 criteria provided, single submitter clinical testing The p.R333C variant (also known as c.997C>T), located in coding exon 9 of the TP53 gene, results from a C to T substitution at nucleotide position 997. The arginine at codon 333 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was first reported in a female meeting Chompret criteria and diagnosed with ALL at age 10 and Ewing sarcoma at age 16 (Mitchell G et al. PLoS ONE 2013; 8(7):e69026). This alteration is located in the tetramerization domain of the p53 protein, and was found to retain transactivation capacity and the ability to form tetramers in yeast based functional studies (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Kawaguchi T et al. Oncogene 2005 Oct; 24(46):6976-81). Additional studies conducted in human cells confirm the ability of p.R333C to form tetramers and showed wild type-like behavior on colony formation, nuclear localization, and growth suppression assays (Fischer NW et al. J. Natl. Cancer Inst., 2018 Jun; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000197833 SCV000254647 uncertain significance Li-Fraumeni syndrome 2020-07-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 333 of the TP53 protein (p.Arg333Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs769934890, ExAC 0.009%). This variant has been reported in an individual affected with acute lymphoblastic leukemia (age 10), and then Ewing sarcoma (age 16) (PMID: 23894400). ClinVar contains an entry for this variant (Variation ID: 184745). This variant has been reported not to substantially affect TP53 protein function (PMID: 12826609, 16007150, 30840781, 29955864). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000485066 SCV000568755 uncertain significance not provided 2017-11-27 criteria provided, single submitter clinical testing This variant is denoted TP53 c.997C>T at the cDNA level, p.Arg333Cys (R333C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant was observed in a patient with a history of acute lymphoblastic leukemia (ALL) and Ewing sarcoma (Mitchell 2013). TP53 Arg333Cys is reported as having functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003) and was shown to maintain the ability to form the p53 tetramer (Kawaguchi 2005). TP53 Arg333Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Arg333Cys is located in the tetramerization domain (Bode 2004). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether TP53 Arg333Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000164055 SCV000686789 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing
Mendelics RCV000197833 SCV000839104 uncertain significance Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780790 SCV000918344 uncertain significance not specified 2018-07-13 criteria provided, single submitter clinical testing Variant summary: TP53 c.997C>T (p.Arg333Cys) results in a non-conservative amino acid change located in the p53, tetramerisation domain (IPR010991) 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 2.4e-05 in 245334 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.997C>T, has been reported in the literature in an individual affected with acute lymphoblastic leukemia (ALL) and Ewing sarcoma, who met the Chompret criteria for Li-Fraumeni Syndrome (Mitchell 2013). This report however does not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome (LFS). In a study evaluating an impact on protein function, the variant protein was found to be able to form tetramers and had a partial transcriptional activity (Kawaguchi 2005), however these data do not allow convincing conclusions about the variant effect. Four 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000989701 SCV001140240 uncertain significance Squamous cell carcinoma of the head and neck 2019-05-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485066 SCV001469931 uncertain significance not provided 2019-12-05 criteria provided, single submitter clinical testing
Baylor Genetics RCV001294069 SCV001482864 uncertain significance Li-Fraumeni syndrome 1 2019-10-12 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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