Submissions for variant NM_000038.6(APC):c.6609T>C (p.Val2203=)

gnomAD frequency: 0.00014  dbSNP: rs149328018

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003650384	SCV000166050	benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000211926	SCV000209480	benign	not specified	2014-08-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000159523	SCV000214020	likely benign	Hereditary cancer-predisposing syndrome	2014-11-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Illumina Laboratory Services, Illumina	RCV000399599	SCV000452039	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000159523	SCV000681810	likely benign	Hereditary cancer-predisposing syndrome	2016-05-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589578	SCV000694099	benign	not provided	2016-03-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589578	SCV000887542	benign	not provided	2021-02-26	criteria provided, single submitter	clinical testing
Mendelics	RCV000987579	SCV001136935	likely benign	Familial adenomatous polyposis 1	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589578	SCV002062612	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	APC: BP4, BP7
Genetic Services Laboratory, University of Chicago	RCV000211926	SCV002066164	benign	not specified	2021-10-11	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000159523	SCV002528809	benign	Hereditary cancer-predisposing syndrome	2020-11-05	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000159523	SCV004014994	likely benign	Hereditary cancer-predisposing syndrome	2023-05-25	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000211926	SCV004025077	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000159523	SCV000693486	likely benign	Hereditary cancer-predisposing syndrome	2017-06-27	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356436	SCV001551602	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The APC p.Val2203= variant was identified in the literature, however, the frequency of this variant in an affected population was not provided. The variant was also identified in ClinVar (3x as Benign by GeneDx, Invitae and Integrated Genetics, 5x as Likely Benign, and 1x as Uncertain). The variant was not identified in LOVD 3.0 or UMD-LSDB. The variant was identified in control databases in 79 of 276074 chromosomes at a frequency of 0.00023, increasing the likelihood that this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23952 chromosomes (freq: 0.00004), Latino in 1 of 34370 chromosomes (freq: 0.00003), European Non-Finnish in 12 of 125826 chromosomes (freq: 0.0001), and Ashkenazi Jewish in 65 of 10124 chromosomes (freq: 0.006). The variant was not observed in the Other, East Asian, Finnish, or South Asian populations. The p.Val2203= 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. In addition, the variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as likely benign.
Clinical Genetics, Academic Medical Center	RCV000211926	SCV002034458	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000589578	SCV002035928	likely benign	not provided		no assertion criteria provided	clinical testing