ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.1151T>C (p.Met384Thr)

gnomAD frequency: 0.00001  dbSNP: rs1060501196
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV000662831 SCV001949910 likely benign Li-Fraumeni syndrome 1 2021-08-04 reviewed by expert panel curation Transactivation assays show retained 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 contributors). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). In summary, TP53 c.1151T>C (p.Met384Thr) 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.
Invitae RCV000462881 SCV000545291 uncertain significance Li-Fraumeni syndrome 2023-10-16 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 384 of the TP53 protein (p.Met384Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 406575). 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. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609). 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.
Ambry Genetics RCV000566404 SCV000665264 likely benign Hereditary cancer-predisposing syndrome 2021-01-07 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.
Counsyl RCV000662831 SCV000785684 uncertain significance Li-Fraumeni syndrome 1 2017-11-01 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000566404 SCV000910156 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-18 criteria provided, single submitter clinical testing This missense variant replaces methionine with threonine at codon 384 of the TP53 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact protein structure and function. Transcriptional transactivation studies in yeast and human cell growth suppression assays have not demonstrated an impact to protein function (PMID: 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251490 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000986047 SCV001134862 uncertain significance not provided 2019-01-17 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000662831 SCV004017863 uncertain significance Li-Fraumeni syndrome 1 2023-04-11 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health RCV000462881 SCV004823711 uncertain significance Li-Fraumeni syndrome 2023-11-02 criteria provided, single submitter clinical testing This missense variant replaces methionine with threonine at codon 384 of the TP53 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. Transcriptional transactivation studies in yeast and human cell growth suppression assays have not demonstrated an impact to protein function (PMID: 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251490 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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