Submissions for variant NM_000038.6(APC):c.3867T>A (p.Cys1289Ter)

dbSNP: rs1554085355

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657604	SCV000779346	pathogenic	not provided	2016-07-14	criteria provided, single submitter	clinical testing	This variant is denoted APC c.3867T>A at the cDNA level and p.Cys1289Ter (C1289X) at the protein level. The substitution creates a nonsense variant, which changes a Cysteine to a premature stop codon (TGT>TGA), and is predicted to cause loss of normal protein function through protein truncation. This variant has been reported in individuals with a clinical diagnosis of Familial Adenomatous Polyposis (FAP) and is considered pathogenic (Won 1999, Kerr 2013).
Fulgent Genetics, Fulgent Genetics	RCV000763543	SCV000894356	pathogenic	Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV003337333	SCV002229736	pathogenic	Familial adenomatous polyposis 1	2022-04-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys1289*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1555 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 10083733). ClinVar contains an entry for this variant (Variation ID: 545962). 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 (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.
Ambry Genetics	RCV002360677	SCV002624788	pathogenic	Hereditary cancer-predisposing syndrome	2019-02-01	criteria provided, single submitter	clinical testing	The p.C1289* pathogenic mutation (also known as c.3867T>A), located in coding exon 15 of the APC gene, results from a T to A substitution at nucleotide position 3867. This changes the amino acid from a cysteine to a stop codon within coding exon 15. This alteration was identified in a Korean patient with polyposis and colorectal cancer but who did not manifest extracolonic features associated with FAP (Kim DW et al. Hum. Mutat. 2005 Sep;26:281; Won YJ et al. J. Hum. Genet. 1999;44:103-8). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003337333	SCV004043227	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.