Submissions for variant NM_000038.6(APC):c.1695A>G (p.Glu565=)

gnomAD frequency: 0.01170  dbSNP: rs77921116

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162514	SCV000212906	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV003650411	SCV000261926	benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000259790	SCV000451991	benign	APC-Associated Polyposis Disorders	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000162514	SCV000681485	benign	Hereditary cancer-predisposing syndrome	2016-03-18	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000202246	SCV000700376	benign	not specified	2017-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000202246	SCV000805372	benign	not specified	2017-01-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000202246	SCV000885020	benign	not specified	2018-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV001711321	SCV001943945	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000162514	SCV002819183	benign	Hereditary cancer-predisposing syndrome	2022-09-08	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV002516439	SCV004017649	benign	Familial adenomatous polyposis 1	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000202246	SCV004024361	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202246	SCV000256931	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000202246	SCV000591085	benign	not specified		no assertion criteria provided	clinical testing	The APC p.Glu565Glu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant is listed in UMD (3X) as a neutral variant (co-occurring with a pathogenic APC variant in one sample), in the ClinVar database (classified as benign by Ambry Genetics), and in the Invitae database (classified as “variant of unknown significance” by Emory Genetics). Three of five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the potential creation of a 5’ splice site; however, this information is not predictive enough to assume pathogenicity. The variant was identified in the literature in 10 of 1695 familial adenomatous polyposis cases (allelic frequency: 0.003); the authors suggest the variant is likely benign due to a co-occurring pathogenic APC variant identified in at least one of these individuals (Kerr 2013). In addition, the variant was identified in several populations at polymorphic allelic frequencies: 1000 Genomes Project (frequency: 0.014), Exome Variant Server ESP project (African American cohort frequency: 0.036, and the ExAC browser (African cohort frequency: 0.038). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
True Health Diagnostics	RCV000162514	SCV000787831	likely benign	Hereditary cancer-predisposing syndrome	2018-01-05	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000202246	SCV001808178	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000202246	SCV001920722	benign	not specified		no assertion criteria provided	clinical testing