ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6383del (p.Ala2128fs) (rs587779803)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115110 SCV000149019 pathogenic not provided 2017-12-26 criteria provided, single submitter clinical testing This deletion of one nucleotide in APC is denoted c.6383delC at the cDNA level and p.Ala2128ValfsX11 (A2128VfsX11) at the protein level. The normal sequence, with the base that is deleted in brackets, is CAAG[delC]TTCG. The deletion causes a frameshift which changes an Alanine to a Valine at codon 2128, and creates a premature stop codon at position 11 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. APC c.6383delC was identified in at least one individual with colon cancer (Susswein 2016). We consider this variant to be pathogenic.
Invitae RCV000697246 SCV000825846 pathogenic Familial adenomatous polyposis 1 2018-06-24 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the APC gene (p.Ala2128Valfs*11). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 716 amino acids of the APC protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with colon cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 127311). This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. A different truncation, c.7932_7935del (p.Tyr2645Lysfs*14), that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). For these reasons, this variant has been classified as Pathogenic.

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