ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.1101-2A>G (rs587781664)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129814 SCV000184628 pathogenic Hereditary cancer-predisposing syndrome 2017-06-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
GeneDx RCV000213070 SCV000211769 likely pathogenic not provided 2018-10-18 criteria provided, single submitter clinical testing This variant is denoted TP53 c.1101-2A>G or IVS10-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 10 of the TP53 gene. TP53 c.1101-2A>G was reported in a child with adrenocortical carcinoma whose tumor was homozygous for the variant, indicating loss of the wild type allele (Pinto 2011). Tumor RNA studies revealed that this variant leads to aberrant splicing, causing a frameshift which is predicted to result in an extended protein (Pinto 2011). The disrupted region includes the C-terminal regulatory domain, which encompasses two nuclear localization signals (Shaulsky 1990, Bode 2004, Pessoa 2014). This variant has also been reported in at least one individual with breast cancer (Susswein 2016). Based on currently available evidence, we consider TP53 c.1101-2A>G to be a likely pathogenic variant.
Invitae RCV000206779 SCV000261653 pathogenic Li-Fraumeni syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 10. It is expected to disrupt mRNA splicing and likely results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with an adenocortical tumor (PMID: 20967502). This variant is also known as IVS10-2 A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 141332). Experimental mRNA studies have shown that this change affects mRNA splicing and results in the deletion of the first 10 nucleotides of exon 11. This generates a frameshift and creates a translational stop signal 82 nucleotides downstream of the wild-type transcript (PMID: 20967502). The C-terminal region of the TP53 protein disrupted by this variant contains amino acid residues important for TP53 regulation and nuclear localization (PMID: 20932800, 26205489). For these reasons, this variant has been classified as Pathogenic.

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