ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6985A>G (p.Ile2329Val) (rs146048493)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000987581 SCV000166054 benign Familial adenomatous polyposis 1 2020-12-04 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 Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Subpopulation frequency in support of benign classification
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 likely benign not specified 2019-02-08 criteria provided, single submitter clinical testing Variant summary: The variant, APC c.6985A>G (p.Ile2329Val) results in a conservative amino acid change located in the Adenomatous polyposis coli protein basic domain 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 0.00027 in 278604 control chromosomes, predominantly at a frequency of 0.0048 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 67 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 a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. The variant, 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 (Azzopard _2008, Martin-Morales _2018). However, these reports 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign (X1)/likely benign (X2). Based on the evidence outlined above, the variant was classified as likely benign.
Color Health, Inc 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 Clinical Services Laboratory,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.
CSER _CC_NCGL, University of Washington RCV000148359 SCV000190049 likely benign Colorectal adenoma 2014-06-01 no assertion criteria provided research

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