Submissions for variant NM_000038.6(APC):c.2677G>T (p.Glu893Ter)

dbSNP: rs199740875

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485943	SCV000568274	pathogenic	not provided	2016-12-01	criteria provided, single submitter	clinical testing	This variant is denoted APC c.2677G>T at the cDNA level and p.Glu893Ter (E893X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA). This variant is predicted to cause loss of normal protein function through protein truncation. This variant has been reported in individuals with Familial Adenomatous Polyposis and is considered pathogenic (Hutter 2001, Kohda 2016).
Color Diagnostics, LLC DBA Color Health	RCV001186210	SCV001352562	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-14	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 16 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000485943	SCV001450064	pathogenic	not provided	2020-01-02	criteria provided, single submitter	clinical testing
Invitae	RCV003335359	SCV001591316	pathogenic	Familial adenomatous polyposis 1	2021-09-29	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). 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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 419997). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 11748858, 19444466, 20685668). This sequence change creates a premature translational stop signal (p.Glu893*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1951 amino acid(s) of the APC protein.
Myriad Genetics, Inc.	RCV003335359	SCV004044770	pathogenic	Familial adenomatous polyposis 1	2023-05-05	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485943	SCV004219120	pathogenic	not provided	2023-02-07	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of APC protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals and families with familial adenomatous polyposis (FAP) (PMIDs: 20685668 (2010), 19444466 (2009), 11748858 (2001)). Based on the available information, this variant is classified as pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000503003	SCV000591115	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Glu893X variant was identified in 4 of 122 proband chromosomes (frequency: 0.03) from individuals or families with colorectal cancer (Hutter 2001, Zauber 2014). The variant was also identified in HGMD, “InSiGHT Colon Cancer Database”, and UMD (5X as an unclassified variant). Of note, this variant occurs in the last exon of the gene and truncating variants in this region are sometimes not subject to nonsense mediated RNA decay, although further study would be needed to verify this. The p.Glu893X variant leads to a premature stop codon at position 893, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of disease in familial adenomatous polyposis and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000485943	SCV000691725	pathogenic	not provided		no assertion criteria provided	clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000786963	SCV000925868	pathogenic	Familial adenomatous polyposis 1	2018-10-19	no assertion criteria provided	clinical testing