Submissions for variant NM_000038.6(APC):c.1660C>T (p.Arg554Ter) (rs137854573)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129303	SCV000184065	pathogenic	Hereditary cancer-predisposing syndrome	2018-03-28	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)
University of Washington Department of Laboratory Medicine,University of Washington	RCV000210172	SCV000266005	pathogenic	Colorectal cancer, susceptibility to	2015-11-20	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000844608	SCV000271308	pathogenic	Familial multiple polyposis syndrome	2019-01-17	criteria provided, single submitter	clinical testing	The p.Arg554X variant in APC has been previously reported in at least 15 individ uals with familial adenomatous polyposis (FAP) (Fodde 1992, Ripa 2002, Friedl 20 05, Rivera 2011, Bisgaard 2004, Truta 2005) and was absent from large population studies. It has also been reported in ClinVar (Variation ID#807). This nonsense variant leads to a premature termination codon at position 554, which is predic ted to lead to a truncated or absent protein. Heterozygous loss of function of t he APC gene is an established disease mechanism in individuals with FAP. In summ ary, this variant meets criteria to be classified as pathogenic for familial ade nomatous polyposis in an autosomal dominant manner. ACMG/AMP Criteria applied: P VS1, PS4, PM2.
GeneDx	RCV000482405	SCV000567480	pathogenic	not provided	2018-04-06	criteria provided, single submitter	clinical testing	This variant is denoted APC c.1660C>T at the cDNA level and p.Arg554Ter (R554X) 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 either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with Familial Adenomatous Polyposis (FAP) (Fodde 1992, van der Luijt 1997, Blaker 2003, Friedl and Aretz 2005, Castellsague 2010) and is considered pathogenic.
Invitae	RCV000000845	SCV000647193	pathogenic	Familial adenomatous polyposis 1	2018-08-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg554*) in the APC gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in numerous individuals affected with familial adenomatous polyposis (PMID: 1324223, 20685668, 15108286, 15951963, 20924072, 12357334, 20223039). ClinVar contains an entry for this variant (Variation ID: 807). Loss-of-function variants in APC are known to be pathogenic (PMID: 20685668, 17963004). For these reasons, this variant has been classified as Pathogenic.
Color	RCV000129303	SCV000686849	pathogenic	Hereditary cancer-predisposing syndrome	2017-08-20	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000763541	SCV000894354	pathogenic	Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma	2018-10-31	criteria provided, single submitter	clinical testing
OMIM	RCV000000845	SCV000020995	pathogenic	Familial adenomatous polyposis 1	1992-08-01	no assertion criteria provided	literature only
Yale Center for Mendelian Genomics,Yale University	RCV000000845	SCV000784633	pathogenic	Familial adenomatous polyposis 1	2015-11-27	no assertion criteria provided	literature only