ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122797 SCV000166054 benign Familial adenomatous polyposis 1 2018-01-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131625 SCV000186647 likely benign Hereditary cancer-predisposing syndrome 2017-12-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Co-occurence with mutation in same gene (phase unknown),Subpopulation frequency in support of benign classification
GeneDx RCV000211933 SCV000209542 likely benign not specified 2017-10-25 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.
Integrated Genetics/Laboratory Corporation of America 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 RCV000131625 SCV000910576 likely benign Hereditary cancer-predisposing syndrome 2016-05-28 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148359 SCV000190049 likely benign Colorectal adenoma 2014-06-01 no assertion criteria provided research

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