ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.1066G>C (p.Gly356Arg)

gnomAD frequency: 0.00001  dbSNP: rs766786605
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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 RCV001723809 SCV001949906 likely benign Li-Fraumeni syndrome 1 2021-08-04 reviewed by expert panel curation 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). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). In summary, TP53 c.1066G>C (p.Gly356Arg) 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: BS3_BS2_Supporting, BP4.
Ambry Genetics RCV000213405 SCV000278550 likely benign Hereditary cancer-predisposing syndrome 2021-06-08 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 RCV000471717 SCV000545298 uncertain significance Li-Fraumeni syndrome 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 356 of the TP53 protein (p.Gly356Arg). This variant is present in population databases (rs766786605, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 234059). 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 RCV000481680 SCV000569810 uncertain significance not provided 2021-08-24 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest no damaging effect: classified as functional based on transactivation assays (Kato 2003); This variant is associated with the following publications: (PMID: 12826609, 14559903)
Color Diagnostics, LLC DBA Color Health RCV000213405 SCV000691572 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-26 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 356 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant is functional in yeast transcriptional activation assays and human cell growth suppression assays (PMID: 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has been identified in 1/245622 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 RCV000781911 SCV000920315 uncertain significance not specified 2018-02-23 criteria provided, single submitter clinical testing Variant summary: TP53 c.1066G>C (p.Gly356Arg) results in a non-conservative amino acid change located in the p53, tetramerisation domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245622 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The c.1066G>C variant has been reported in the literature, but this report does not provide strong evidence about an association of the variant with Li-Fraumeni Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481680 SCV004221344 uncertain significance not provided 2023-06-13 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in individuals at risk for Li-Fraumeni syndrome (PMID: 28861920 (2017)). The variant was found in a healthy individual in a large breast cancer association study (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/TP53)). Experimental studies report the variant does not impact TP53 function (PMIDs: 30224644 (2018), 12826609 (2003)). The frequency of this variant in the general population, 0.000004 (1/250802 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences RCV003919893 SCV004730558 likely benign TP53-related disorder 2022-02-16 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
All of Us Research Program, National Institutes of Health RCV000471717 SCV004823721 uncertain significance Li-Fraumeni syndrome 2023-08-15 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 356 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study in yeast has shown that this variant does not impair the transcriptional transactivation activity of the TP53 protein (IARC database; PMID: 12826609). This variant has been observed in a tumor sample from an individual affected with triple-negative breast cancer (PMID: 24356096). This variant has been identified in 1/245622 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.
True Health Diagnostics RCV000213405 SCV000788222 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-22 no assertion criteria provided clinical testing

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