ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4009_4010dup (p.Gln1338fs) (rs1554085450)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000542134 SCV000647488 pathogenic Familial adenomatous polyposis 1 2017-05-22 criteria provided, single submitter clinical testing This sequence change inserts 2 nucleotides in exon 16 of the APC mRNA (c.4009_4010dupCT), causing a frameshift at codon 1338. This creates a premature translational stop signal in the last exon of the APC mRNA (p.Gln1338Cysfs*78). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1507 amino acids of the APC protein. This variant removes the final portion of the C-terminus of the APC protein, including the Basic domain, the EB1 binding site, and the HDLG binding site, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While this variant has not been reported in the literature, different truncations downstream of this variant, p.Asp1942Glufs*27 and p.Asp1979Thrfs*64, have been observed in individuals and families affected with familial adenomatous polyposis and are considered pathogenic (PMID: 20434453, 9824584, 15108286, 11001924). 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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