ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4666dup (p.Thr1556fs) (rs587783031)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491894 SCV000579826 pathogenic Hereditary cancer-predisposing syndrome 2016-05-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Rarity in general population databases (dbsnp, esp, 1000 genomes)
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000500725 SCV000591177 uncertain significance not specified 2015-01-07 criteria provided, single submitter clinical testing
National Molecular Genetics Centre of Cancer Research,N.N. Alexandrov National Cancer Centre of Belarus RCV000656377 SCV000778309 pathogenic Familial adenomatous polyposis 1 2018-05-30 criteria provided, single submitter clinical testing Detected in patient with clinical features of Gardner syndrome. Emory Genetics Laboratory Classification Definitions Pathogenic: a. Variants predicted to result in the loss of protein function in a gene for which this is a known mechanism of disease (may or may not have been previously reported in patients with disease) 1. frameshift (an insertion or deletion that is not a multiple of 3 nucleotides).
Invitae RCV000656377 SCV000941363 pathogenic Familial adenomatous polyposis 1 2018-10-30 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the APC gene (p.Thr1556Asnfs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1288 amino acids of the APC protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with familial adenomatous polyposis (PMID: 9101302, 17411426, 19029688, 20685668, 20924072, 21110124, 26511139), and has been shown to segregate with disease in a family (PMID: 11852337). This variant is also known as 4663insA in the literature. ClinVar contains an entry for this variant (Variation ID: 428112). An experimental study in yeast has shown that this variant fails to inhibit the transcription mediated by the beta_x0001_-catenin/TCF4 complex (PMID: 14633595). This variant is expected to delete a portion of the C-terminal region of the APC protein, including the basic domain, the EB1 binding site (residues Pro2559-His2770) and the HDLG binding site (residues Ser2771-Val2843), which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). Different truncations (p.Arg1943Lysfs*28 and p.Asn1979Thrfs*64) that lie downstream of this variant have been determined to be pathogenic (PMID: 21779980, 20434453, 9824584, 26681312). This suggests that deletion of this region of the APC protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000583680 SCV000691753 pathogenic not provided no assertion criteria provided clinical testing

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