Submissions for variant NM_000038.6(APC):c.3593C>G (p.Ser1198Ter)

dbSNP: rs879254089

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236148	SCV000293417	pathogenic	not provided	2015-12-22	criteria provided, single submitter	clinical testing	This variant is denoted APC c.3593C>G at the cDNA level and p.Ser1198Ter (S1198X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TGA) , and is predicted to cause loss of normal protein function through protein truncation. APC Ser1198Ter results in the loss of 1646 amino acids and several protein domains are disrupted by the truncation (Azzopardi 2008, UniProt). This variant has been reported in association with familial adenomatous polyposis (Wallis 1994, Friedl 2005) and is considered pathogenic.
Invitae	RCV003535656	SCV003439216	pathogenic	Familial adenomatous polyposis 1	2023-01-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. 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. ClinVar contains an entry for this variant (Variation ID: 246086). This premature translational stop signal has been observed in individual(s) with clinical features of familial adenomatous polyposis (PMID: 7959691, 27623068). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser1198*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1646 amino acid(s) of the APC protein.
Myriad Genetics, Inc.	RCV002519827	SCV004044683	pathogenic	Familial adenomatous polyposis 1	2023-05-09	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.