Submissions for variant NM_000038.6(APC):c.2483del (p.Thr828fs)

dbSNP: rs886042600

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000484336	SCV000335359	pathogenic	not provided	2017-09-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000484336	SCV000564567	pathogenic	not provided	2014-11-13	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in APC is denoted c.2483delC at the cDNA level and p.Thr828IlefsX14 (T828IfsX14) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AATA[C]TACA. The deletion causes a frameshift, which changes a Threonine to an Isoleucine at codon 828, and creates a premature stop codon at position 14 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. APC c.2483delC has been observed in a individual with a clinical diagnosis of familial adenomatous polyposis (Friedl 2001). we consider this variant to be pathogenic.
Ambry Genetics	RCV000491139	SCV000579890	pathogenic	Hereditary cancer-predisposing syndrome	2018-09-25	criteria provided, single submitter	clinical testing	The c.2483delC pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of one nucleotide at nucleotide position 2483, causing a translational frameshift with a predicted alternate stop codon (p.T828Ifs*14). This mutation has been reported in a patient with clinical diagnosis of Familial Adenomatous Polyposis (FAP) Syndrome (Friedl W et al. Gut 2001 Apr; 48(4):515-21). 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.
Invitae	RCV003337270	SCV000768196	pathogenic	Familial adenomatous polyposis 1	2019-10-03	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. This variant has been reported in an individual affected with familial adenomatous polyposis (PMID: 11247896). ClinVar contains an entry for this variant (Variation ID: 283339). 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.Thr828Ilefs*14). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2016 amino acids (~70%) of the APC protein.
Myriad Genetics, Inc.	RCV003337270	SCV004044894	pathogenic	Familial adenomatous polyposis 1	2023-05-04	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.