Submissions for variant NM_000038.6(APC):c.2950G>T (p.Glu984Ter)

dbSNP: rs1254176854

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002524127	SCV002228180	pathogenic	Familial adenomatous polyposis 1	2021-02-22	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. 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. This variant has been observed in individual(s) with clinical features of familial adenomatous polyposis (FAP) (PMID: 20685668, 11748858, 19444466). This variant is also known as 2677G>T E893X in the literature. ClinVar contains an entry for this variant (Variation ID: 433638). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu984*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1860 amino acid(s) of the APC protein.
Myriad Genetics, Inc.	RCV002524127	SCV004043288	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000500319	SCV000591125	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Glu984* variant was not identified in the literature nor was it identified in the dbSNP, MutDB, or the Zhejiang University database. The variant was identified in ClinVar (classified as pathogenic by COGR), Cosmic (7x in large intestine or pancreas), LOVD 3.0 (1x), and in UMD-LSDB (2x as causal). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Glu984* variant leads to a premature stop codon at position 984, 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.