ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1825G>A (p.Val609Ile) (rs147863331)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000417366 SCV000148979 likely benign not specified 2018-01-12 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 RCV000115070 SCV000186859 likely benign Hereditary cancer-predisposing syndrome 2017-08-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,Co-occurence with mutation in same gene (phase unknown)
Invitae RCV000198802 SCV000253992 likely benign Familial adenomatous polyposis 1 2017-12-14 criteria provided, single submitter clinical testing
Counsyl RCV000198802 SCV000488039 uncertain significance Familial adenomatous polyposis 1 2015-12-18 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000417366 SCV000591092 likely benign not specified 2013-01-17 criteria provided, single submitter clinical testing
Color RCV000115070 SCV000681488 likely benign Hereditary cancer-predisposing syndrome 2016-04-22 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679049 SCV000805373 likely benign not provided 2017-06-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000417366 SCV000918451 benign not specified 2018-11-19 criteria provided, single submitter clinical testing Variant summary: APC c.1825G>A (p.Val609Ile) results in a conservative amino acid change located in the Armadillo of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 277028 control chromosomes. The observed variant frequency is approximately 4.19 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.1825G>A has been reported in the literature in individuals affected with colorectal cancer, Lynch syndrome, breast cancer, and other unspecified phenotypes (Kerr_2013, Liang_2016, Pearlman_2016, Yurgelun_2017, Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Co-occurrences with other pathogenic variant(s) have been reported (TP53 c.742C>T, p.Arg248Trp; APC c.3927_3931delAAAGA, p.Glu1309fsX4, internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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.

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