Submissions for variant NM_000038.6(APC):c.3569C>A (p.Ser1190Ter)

dbSNP: rs886039618

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255278	SCV000322536	likely pathogenic	not provided	2016-04-18	criteria provided, single submitter	clinical testing	This variant is denoted APC c.3569C>A at the cDNA level and p.Ser1190Ter (S1190X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TAA), and is predicted to cause loss of normal protein function through protein truncation. Even though this variant occurs in the last exon, and nonsense-mediated decay is not expected to occur, it is significant since the last 1653 amino acids are no longer translated. Furthermore, the truncation would disrupt several functional domains and binding motifs (Azzopardi 2008, UniProt). This variant has been reported in at least one individual with FAP (Segditsas 2008) and is considered likely pathogenic.
Invitae	RCV002229727	SCV001578050	pathogenic	Familial adenomatous polyposis 1	2020-01-24	criteria provided, single submitter	clinical testing	A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that deletion of this region of the APC protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. 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 has not been reported in the literature in individuals with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 265551). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the APC gene (p.Ser1190*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1654 amino acids of the APC protein.