ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5140G>A (p.Asp1714Asn) (rs148275069)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122784 SCV000166041 likely benign Familial adenomatous polyposis 1 2019-12-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129088 SCV000183796 likely benign Hereditary cancer-predisposing syndrome 2018-07-26 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000479916 SCV000564574 likely benign not specified 2017-11-22 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587086 SCV000600110 likely benign not provided 2019-08-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000479916 SCV000694069 likely benign not specified 2020-07-16 criteria provided, single submitter clinical testing Variant summary: APC c.5140G>A (p.Asp1714Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 250168 control chromosomes, predominantly at a frequency of 0.00035 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5-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 Non-Finnish European origin. c.5140G>A has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (e.g. Azzopardi_2008, Out_2015, Rohlin_2017) but has also been reported in patients with other phenotypes, including breast cancer and medulloblastoma (e.g. Tung_2015, Zhang_2015). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Experimental evidence evaluating an impact on protein function, demonstrated the variant alters beta-catenin-regulated transcription (CRT) in vitro (e.g. Azzopardi_2008). However, no definitive conclusions can be drawn about the clinical relevance of this finding. Eight ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=5) and as uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000587086 SCV000805422 uncertain significance not provided 2014-03-11 criteria provided, single submitter clinical testing
Mendelics RCV000122784 SCV000838131 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000129088 SCV000910666 likely benign Hereditary cancer-predisposing syndrome 2016-11-22 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000587086 SCV001154471 uncertain significance not provided 2017-02-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001157159 SCV001318706 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 RCV000122784 SCV000190065 uncertain significance Familial adenomatous polyposis 1 2014-06-01 no assertion criteria provided research

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