ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.783-2A>C

dbSNP: rs1060501207
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001203239 SCV001374394 pathogenic Li-Fraumeni syndrome 2019-10-11 criteria provided, single submitter clinical testing 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. This sequence change affects an acceptor splice site in intron 7 of the TP53 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in families with Li-Fraumeni syndrome (PMID: 26014290, 27501770, Invitae). ClinVar contains an entry for this variant (Variation ID: 635386). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002406716 SCV002670837 pathogenic Hereditary cancer-predisposing syndrome 2020-06-01 criteria provided, single submitter clinical testing The c.783-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 7 in the TP53 gene. This nucleotide position is highly conserved in available vertebrate species. Two other alteration at this same splice acceptor (c.783-2A>G and c.783-1G>A) have been identified in patients meeting LFS or Chompret criteria (Bougeard G et al. J. Clin. Oncol., 2015 Jul;33:2345-52; Ambry internal data). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
MutSpliceDB: a database of splice sites variants effects on splicing, NIH RCV000786821 SCV000925714 not provided not provided no assertion provided in vitro

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