ClinVar Miner

Submissions for variant NM_001126112.2(TP53):c.1121del (p.Gly374fs) (rs878854063)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000233345 SCV000285172 uncertain significance Li-Fraumeni syndrome 2018-04-30 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 11 of the TP53 mRNA (c.1121delG), causing a frameshift at codon 374 (p.Gly374Valfs*48). This is expected to replace the last 20 amino acids of the TP53 protein with 47 different amino acids residues, creating a new downstream translational stop signal that extends the length of the protein by 27 amino acids. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 237940). This variant disrupts a portion of the C-terminal regulatory domain (residues 363-393) of TP53 that is necessary for full TP53 DNA binding and transactivation activity (PMID: 22178617, 25794615, 26205489). This suggests that disruption of this region may affect protein function, but experiments have not been done to test for this variant. In summary, this is a rare frameshift variant in the last exon of TP53 that is expected to disrupt a domain necessary for proper protein function. However, additional data is needed to prove that conclusively. Therefore, this variant has been classified as Variant of Uncertain Significance.

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