ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4389dup (p.Glu1464fs) (rs1554085850)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000646479 SCV000768251 pathogenic Familial adenomatous polyposis 1 2018-02-16 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the APC gene (p.Glu1464Argfs*5). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1380 amino acids of the APC protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with APC-related disease. This variant is expected to delete a portion of the C-terminal region of the APC protein, including the EB1 binding site (residues Pro2559-His2770) and the HDLG binding site (residues Ser2771-Val2843), which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). Although functional studies have not been performed for this variant, a downstream truncating variant, c.7932_7935del (p.Tyr2645Lysfs*14), has been reported in several individuals with familial adenomatous polyposis (FAP), attenuated FAP, and desmoid tumors (PMID: 1316610, 8381579, 9824584, 22135120, 27081525). This suggests that deletion of the EB1 and HDLG binding sites of the APC protein are causative of disease. For these reasons, this variant has been classified as Pathogenic.

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