Submissions for variant NM_000038.6(APC):c.4897dup (p.Thr1633fs)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004565535	SCV004320547	pathogenic	Familial adenomatous polyposis 1	2023-08-28	criteria provided, single submitter	clinical testing	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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the APC protein in which other variant(s) (p.Tyr2645Lysfs*14) have been determined to be pathogenic (PMID: 1316610, 8381579, 9824584, 22135120, 27081525; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr1633Asnfs*5) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1211 amino acid(s) of the APC protein.