ClinVar Miner

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

dbSNP: rs769934890
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Total submissions: 11
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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 likely benign Hereditary cancer-predisposing syndrome 2021-11-19 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV000197833 SCV000254647 uncertain significance Li-Fraumeni syndrome 2023-12-28 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 333 of the TP53 protein (p.Arg333Cys). This variant is present in population databases (rs769934890, gnomAD 0.004%). This missense change has been observed in individual(s) with acute lymphoblastic leukemia, breast cancer, Ewing sarcoma, pancreatic cancer, and/or rectal cancer (PMID: 23894400, 31321604, 33128190). ClinVar contains an entry for this variant (Variation ID: 184745). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 30224644). 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 2019-05-24 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22187033, 24030381, 30352134, 28861920, 16007150, 26572807, 23894400, 27834926, 27347428, 28993836, 28098136, 14559903, 12826609, 29955864, 30840781, 31016814, 31321604)
Color Diagnostics, LLC DBA Color Health RCV000164055 SCV000686789 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-01 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 333 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). Experimental studies have reported for this variant behaves as wildtype in a yeast-based transcriptional transactivation assay and a human cell growth suppression assay (PMID: 12826609, 30224644), but demonstrated intermediate level activity in a colony suppression assay (PMID: 30840781). This variant has been reported in an individual affected with early-onset breast cancer (PMID: 33128190) and an individual affected with Ewing sarcoma and leukemia (IARC database, PMID: 27328919). This variant has been identified in 6/250508 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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 benign Squamous cell carcinoma of the head and neck 2023-08-22 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].
PreventionGenetics, part of Exact Sciences RCV003407609 SCV004112940 uncertain significance TP53-related disorder 2023-06-08 criteria provided, single submitter clinical testing The TP53 c.997C>T variant is predicted to result in the amino acid substitution p.Arg333Cys. This variant has been reported in patients with adult onset sarcoma, rectal and pancreatic cancer, and breast and/or ovarian cancer, although pathogenicity was not established in these cases (Mitchell et al. 2013. PubMed ID: 23894400; Bittar et al. 2019. PubMed ID: 31321604; Gomes et al. 2020. PubMed ID: 33128190). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7574030-G-A). This variant is interpreted as likely benign by the ClinGen TP53 Variant Curation Expert Panel, in part based on detection of this variant in 3 individuals over the age of 60 without cancer and functional studies not supporting a deleterious effect (https://www.ncbi.nlm.nih.gov/clinvar/variation/184745/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health RCV000197833 SCV004823736 uncertain significance Li-Fraumeni syndrome 2023-11-30 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 333 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). Experimental studies have reported for this variant behaves as wildtype in a yeast-based transcriptional transactivation assay and a human cell growth suppression assay (PMID: 12826609, 30224644), but demonstrated intermediate level activity in a colony suppression assay (PMID: 30840781). This variant has been reported in an individual affected with early-onset breast cancer (PMID: 33128190) and an individual affected with Ewing sarcoma and leukemia (IARC database, PMID: 27328919). This variant has been identified in 6/250508 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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