ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4348C>T (p.Arg1450Ter) (rs121913332)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000486553 SCV000226390 pathogenic not provided 2014-06-05 criteria provided, single submitter clinical testing
Invitae RCV000174977 SCV000259527 pathogenic Familial adenomatous polyposis 1 2018-01-18 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the APC gene (p.Arg1450*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 1394 amino acids of the APC protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with familial adenomatous polyposis (FAP), non-FAP colorectal cancer, and multiple adenomas (PMID: 8103406, 8730280, 8990002, 9950360, 20223039, 20924072, 21110124). ClinVar contains an entry for this variant (Variation ID: 194585). This variant is expected to delete a large portion of the C-terminal region of the APC protein, including the EB1 binding site (residues Pro2559-His2770) and the HDLG binding site (residues Ser2771-Val2843), which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). Although functional studies have not been performed for this variant, several downstream truncating variants have been reported in individuals with familial adenomatous polyposis (FAP). 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 RCV000486553 SCV000568280 pathogenic not provided 2016-08-09 criteria provided, single submitter clinical testing This variant is denoted APC c.4348C>T at the cDNA level and p.Arg1450Ter (R1450X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA). Even though nonsense-mediated decay is not expected to occur due to the position of the variant, it is significant since the last 1394 amino acids are no longer translated correctly and is predicted to cause loss of normal protein function through protein truncation. This variant has been reported in individuals with histologically verified Familial Adenomatous Polyposis (Dobbie 1996, Wallis 1999, Latchford 2007, Kattentidt Mouravieva 2012). We consider it to be pathogenic.
Ambry Genetics RCV000494198 SCV000581416 pathogenic Hereditary cancer-predisposing syndrome 2017-12-06 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)
Center for Human Genetics, Inc RCV000659277 SCV000781076 pathogenic Familial adenomatous polyposis 2016-11-01 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000441954 SCV000505005 likely pathogenic Neoplasm of the large intestine 2015-07-14 no assertion criteria provided literature only
Yale Center for Mendelian Genomics,Yale University RCV000174977 SCV000784634 pathogenic Familial adenomatous polyposis 1 2015-11-27 no assertion criteria provided literature only

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