ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3146G>A (p.Trp1049Ter) (rs876658667)

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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 RCV000216288 SCV000274214 pathogenic Hereditary cancer-predisposing syndrome 2015-03-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508021 SCV000602538 pathogenic not specified 2017-03-24 criteria provided, single submitter clinical testing
Invitae RCV000530296 SCV000647430 pathogenic Familial adenomatous polyposis 1 2018-12-23 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the APC mRNA at codon 1049 (p.Trp1049*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 1,795 amino acids of the APC protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with familial adenomatous polyposis (PMID: 12010888, 20685668, 20223039). ClinVar contains an entry for this variant (Variation ID: 230610). This variant removes the basic domain, the EB1 binding site, and the HDLG binding site, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). Other truncating variants downstream of this variant (p.Gln1062* and p.Arg1450*) have been determined to be pathogenic (PMID: 1316610, 8162022, 15771908, 8103406, 8730280, 8990002, 9950360, 20223039, 20924072, 21110124). While functional studies have not been performed to directly test the effect of this variant on APC protein function, these observations suggest that deletion of the C-terminal portion of the APC protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

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