ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.943T>A (p.Ser315Thr)

gnomAD frequency: 0.00001  dbSNP: rs762620193
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV000793553 SCV001737918 likely benign Li-Fraumeni syndrome 2020-09-04 reviewed by expert panel curation This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Additionally, 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). In summary, TP53 c.943T>A; p.Ser315Thr 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: BP4 and BS3.
Ambry Genetics RCV000164586 SCV000215245 likely benign Hereditary cancer-predisposing syndrome 2020-01-17 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.
Color Diagnostics, LLC DBA Color Health RCV000164586 SCV000908779 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-10 criteria provided, single submitter clinical testing
Invitae RCV000793553 SCV000932911 uncertain significance Li-Fraumeni syndrome 2023-10-30 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 315 of the TP53 protein (p.Ser315Thr). This variant is present in population databases (rs762620193, gnomAD 0.009%). 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: 185212). 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, 29979965, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001255575 SCV001432066 uncertain significance not specified 2020-08-31 criteria provided, single submitter clinical testing Variant summary: TP53 c.943T>A (p.Ser315Thr) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251474 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.943T>A in individuals affected with Li-Fraumeni Syndrome has been reported. In an experimental study, the variant was reported to not impair transcriptional activity of the TP53 protein based on eight different promoters measured in a yeast assay (Kato_2003). Three 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.
Sema4, Sema4 RCV000164586 SCV002532729 uncertain significance Hereditary cancer-predisposing syndrome 2021-06-24 criteria provided, single submitter curation
PreventionGenetics, part of Exact Sciences RCV003895130 SCV004713066 likely benign TP53-related disorder 2021-11-03 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).

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