Submissions for variant NM_000038.6(APC):c.3732A>G (p.Gln1244=)

gnomAD frequency: 0.01174  dbSNP: rs74380081

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162515	SCV000212907	benign	Hereditary cancer-predisposing syndrome	2014-08-14	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	RCV003650412	SCV000261927	benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000260692	SCV000452008	benign	APC-Associated Polyposis Disorders	2018-01-12	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	RCV000162515	SCV000681629	benign	Hereditary cancer-predisposing syndrome	2016-03-18	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000500807	SCV000700377	benign	not specified	2017-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000500807	SCV000805402	benign	not specified	2017-01-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000500807	SCV000885021	benign	not specified	2018-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV001711429	SCV001939929	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000162515	SCV002819184	benign	Hereditary cancer-predisposing syndrome	2022-09-08	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV002516440	SCV004017660	benign	Familial adenomatous polyposis 1	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000500807	SCV004024367	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000500807	SCV000591154	benign	not specified		no assertion criteria provided	clinical testing	The APC p.Gln1244Gln 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 was identified in the dbSNP (ID: rs74380081) “with benign allele”, the ClinVar database (classified as “benign” by Ambry Genetics), the Clinvitae database (classified as a “variant of unknown significance by Emory Genetics), and the UMD (3X, classified as “likely neutral”). In the UMD database, the variant was identified with a co-occurring pathogenic APC variant (c.4666delA (p.Thr1556LeufsX9)), increasing the likelihood that the p.Gln1244Gln variant does not have clinical significance. In addition, the variant was identified in several populations at polymorphic allelic frequencies: 1000 Genomes Project (frequency: 0.014), the African population in the Exome Aggregation Consortium (ExAC) database (frequency: 0.038), and the African American cohort of the Exome Variant Server ESP Project (frequency: 0.036). The variant was not identified in the literature, nor was it identified in any of the following databases: InSiGHT Colon Cancer Gene Variant Database, “Zhejiang Colon Cancer Database”, GeneInsight COGR database, COSMIC. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the creation of a potential cryptic 3’ (splice donor) site; however, this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000500807	SCV000691742	benign	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162515	SCV000787835	likely benign	Hereditary cancer-predisposing syndrome	2018-01-05	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000500807	SCV001808727	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000500807	SCV001925174	benign	not specified		no assertion criteria provided	clinical testing