ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.375G>T (p.Thr125=) (rs55863639)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229813 SCV000285191 likely pathogenic Li-Fraumeni syndrome 2016-03-13 criteria provided, single submitter clinical testing This sequence change affects codon 125 of the TP53 mRNA. Although this substitution is 'silent', meaning it does not alter the encoded amino acid sequence of the TP53 protein, it changes the last nucleotide of exon 4 and falls within the consensus donor splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with Li-Fraumeni Syndrome (PMID: 11420676). Molecular studies indicate that this c.375G>T substitution disrupts splicing of the TP53 mRNA and likely results in an absent or non-functional protein (PMID: 11420676, 25730903). Two additional variants at this position (c.375G>A and c.375G>C) have been reported in individuals with Li-Fraumeni Syndrome (PMID: 11420676, 1467311, 22170717, 20127978, 10864200, 24382691, 9242456). In two families, the c.375G>A variant was shown to segregate with TP53-related cancers (PMID: 9242456, 1467311). Importantly, the c.375G>A and c.375G>T variants have been shown to have a similar effect on splicing (PMID: 11420676), which suggests these two variants may have a similar role in disease. In summary, this variant is a rare silent change that has been shown to disrupt mRNA splicing. It has not been observed in the general population and has been reported in an individual with Li-Fraumeni Syndrome. A similar silent change with the same effect on mRNA splicing has been reported to segregate with disease. For these reasons, this variant has been classified as Likely Pathogenic.
MutSpliceDB: a database of splice sites variants effects on splicing,NIH RCV000786841 SCV000925738 not provided not provided no assertion provided in vitro

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