ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2626C>T (p.Arg876Ter) (rs121913333)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198823 SCV000253729 pathogenic Familial adenomatous polyposis 1 2018-03-10 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the APC mRNA at codon 876 (p.Arg876*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 1,968 amino acids of the APC protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in many individuals and families affected with familial adenomatous polyposis (PMID: 8187091, 12581900, 20223039, 19029688, 17411426, 14961559). ClinVar contains an entry for this variant (Variation ID: 216014). Several different truncations downstream of this variant (p.Ser932*, p.Ala1050Glufs*6, p.Gln1062*) have been determined to be pathogenic (PMID: 20685668, 23460355, 15771908). 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.
GeneDx RCV000236362 SCV000293420 pathogenic not provided 2018-12-27 criteria provided, single submitter clinical testing This variant is denoted APC c.2626C>T at the cDNA level and p.Arg876Ter (R876X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through protein truncation. Even though this frameshift occurs in the last exon of the gene, and nonsense-mediated decay is not expected to occur, it is significant since the last 1968 amino acids are no longer translated. This variant has been reported in association with familial adenomatous polyposis (FAP) (Miyaki 1994, De Rosa 2003, Mihalatos 2003, De Rosa 2004, Plawski 2004, Friedl 2005, Strekrova 2007, Kerr 2013, Hashimoto 2015, Zhang 2016). Additionally, this variant has been identified in individuals described as having a 'severe' or 'aggressive' phenotype, defined as having more than 1,000 polyps or 5,000 polyps respectively, and in individuals with extracolonic manifestations including medulloblastoma, gastric polyps, and congenital hypertrophy of the retinal pigment epithelium (CHRPE) (De Rosa 2003, Mihalatos 2003, De Rosa 2004, Hashimoto 2015). This variant is considered pathogenic.
Ambry Genetics RCV000492041 SCV000579769 pathogenic Hereditary cancer-predisposing syndrome 2016-08-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000500904 SCV000591114 pathogenic Familial adenomatous polyposis 2015-03-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236362 SCV001133313 pathogenic not provided 2018-11-23 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Database of Curated Mutations (DoCM) RCV000438475 SCV000504996 likely pathogenic Neoplasm of the large intestine 2015-07-14 no assertion criteria provided literature only

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