Submissions for variant NM_000038.6(APC):c.6985A>G (p.Ile2329Val)

gnomAD frequency: 0.00015  dbSNP: rs146048493

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000987581	SCV000166054	benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131625	SCV000186647	likely benign	Hereditary cancer-predisposing syndrome	2019-01-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
GeneDx	RCV001719892	SCV000209542	likely benign	not provided	2021-09-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25203624, 25801821, 26332594, 25980754, 25637381, 18199528, 21859464)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211933	SCV000694106	benign	not specified	2023-03-30	criteria provided, single submitter	clinical testing	Variant summary: APC c.6985A>G (p.Ile2329Val) results in a conservative amino acid change located in the Adenomatous polyposis coli protein basic domain (IPR009234) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 252890 control chromosomes. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is benign. c.6985A>G has been reported in the literature in individuals affected with Lynch syndrome associated cancer and individuals who were high risk for colorectal cancer (example, Azzopardi_2008, Martin-Morales _2018). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000131625	SCV000910576	likely benign	Hereditary cancer-predisposing syndrome	2016-05-28	criteria provided, single submitter	clinical testing
Mendelics	RCV000987581	SCV001136940	benign	Familial adenomatous polyposis 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001151806	SCV001312976	uncertain significance	APC-Associated Polyposis Disorders	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV001719892	SCV001961895	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	APC: BS1, BS2
Sema4, Sema4	RCV000131625	SCV002535146	likely benign	Hereditary cancer-predisposing syndrome	2021-08-03	criteria provided, single submitter	curation
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153405	SCV003843484	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131625	SCV004014927	benign	Hereditary cancer-predisposing syndrome	2023-03-09	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000211933	SCV004243256	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148359	SCV000190049	likely benign	Colorectal adenoma	2014-06-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003905173	SCV004722576	benign	APC-related disorder	2019-07-30	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).