ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5952_5955del (p.Glu1985fs) (rs1057517544)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411671 SCV000488117 likely pathogenic Familial adenomatous polyposis 1 2015-12-30 criteria provided, single submitter clinical testing
Invitae RCV000411671 SCV000552661 likely pathogenic Familial adenomatous polyposis 1 2016-08-12 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotides from exon 16 of the APC mRNA (c.5952_5955delTGAA), causing a frameshift at codon 1985. This creates a premature translational stop signal in the last exon of the APC mRNA (p.Glu1985Leufs*58). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated APC protein. Loss-of-function variants in APC are known to be pathogenic. This particular variant has been reported in the literature in an individual suspected of familial adenomatous polyposis (FAP) (PMID: 20223039). This variant removes the Basic Domain, the EB1 Binding Site, and the HDLG Binding Site of the APC protein, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect of this variant on APC protein function, a different truncating variant, c.7932_7935del (p.Tyr2645Lysfs*14), that only removes the EB1 and HDLG binding sites has been reported in several individuals with familial adenomatous polyposis (FAP) and attenuated FAP (PMID: 1316610, 8381579, 9824584, 22135120). These observations suggest that the C-terminal portion of the protein is clinically important. For these reasons, this variant has been classified as Likely Pathogenic.

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