ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1691G>A (p.Arg564Gln) (rs747418061)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213578 SCV000277820 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000525244 SCV000647195 uncertain significance Familial adenomatous polyposis 1 2018-08-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 564 of the APC protein (p.Arg564Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs747418061, ExAC 0.05%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 233448). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000213578 SCV000681484 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779711 SCV000916466 uncertain significance not specified 2018-04-13 criteria provided, single submitter clinical testing Variant summary: APC c.1691G>A (p.Arg564Gln) results in a conservative amino acid change located in the Armadillo repeat of 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 3.3e-05 in 246076 control chromosomes. This frequency is not higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (3.3e-05 vs 7.1e-05), allowing no conclusion about variant significance. However, the variant is most prevalent in the East Asian subpopulation (5/17234 chromosomes), which exceeds the maximal expected allele frequency for a pathogenic APC variant by 4 fold, suggesting a bening outcome. c.1691G>A has been reported in the literature (Sapari_2014), however, this report does not provide unequivocal conclusions about an 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 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS.

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