ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4025dup (p.Leu1342fs) (rs863225351)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000202185 SCV000778917 pathogenic not provided 2018-01-10 criteria provided, single submitter clinical testing This duplication of one nucleotide in APC is denoted c.4025dupT at the cDNA level and p.Leu1342PhefsX12 (L1342FfsX12) at the protein level. The normal sequence, with the base that is duplicated in brackets, is AGTT[dupT]ATCT. The duplication causes a frameshift which changes a Leucine to a Phenylalanine at codon 1342, and creates a premature stop codon at position 12 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. APC c.4025dupT, also reported as a one base pair insertion in codon 1341, has been reported in several individuals with Familial Adenomatous Polyposis (Gebert 1999, Su 2000, Friedl 2005). We consider this variant to be pathogenic.
Invitae RCV000802754 SCV000942597 pathogenic Familial adenomatous polyposis 1 2018-12-18 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the APC gene (p.Leu1342Phefs*12). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1502 amino acids of the APC protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with familial adenomatous polyposis (PMID: 10077047, 10982189). ClinVar contains an entry for this variant (Variation ID: 217976). 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. This variant disrupts the C-terminus of the APC protein. Other variant(s) that disrupt this region (p.Tyr2645Lysfs*14) have been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202185 SCV000256985 pathogenic not provided no assertion criteria provided research

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