ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.375+6T>C (rs730881998)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000161023 SCV000211742 uncertain significance not provided 2014-04-29 criteria provided, single submitter clinical testing This variant is denoted TP53 c.375+6T>C, or IVS4+6T>C, and consists of a T>C nucleotide substitution at the +6 position of intron 4 of the TP53 gene. Multiple in silico models predict this variant to weaken or destroy the nearby natural donor site and to possibly cause abnormal gene splicing. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. TP53 c.375+6T>C occurs at a base that is moderately conserved across species and was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Based on currently available information, it is unclear whether TP53 c.375+6T>C is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000533123 SCV000629812 uncertain significance Li-Fraumeni syndrome 2018-09-21 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the TP53 gene. It does not directly change the encoded amino acid sequence of the TP53 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 182927). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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