ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4765C>G (p.Arg1589Gly) (rs72541813)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131191 SCV000186141 likely benign Hereditary cancer-predisposing syndrome 2018-03-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance,Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,Other data supporting benign classification,No disease association in small case-control study
GeneDx RCV000211915 SCV000209469 uncertain significance not provided 2017-09-13 criteria provided, single submitter clinical testing This variant is denoted APC c.4765C>G at the cDNA level, p.Arg1589Gly (R1589G) at the protein level, and results in the change of an Arginine to a Glycine (CGT>GGT). This variant has been reported in at least one individual with multiple adenomatous colon polyps (Urso 2013). However, it has also been reported in a colorectal adenoma case-control study where APC Arg1589Gly was present in 1/969 healthy control individuals, but absent in 691 polyposis cases (Azzopardi 2008). APC Arg1589Gly was observed at an allele frequency of 0.012% (8/66496) in individuals of European (Non-Finnish) ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Arg1589Gly occurs at a position that is not conserved and is located in the SAMP repeat/axin binding domain and 20-amino acid repeat beta-catenin down-regulating domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC Arg1589Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000232313 SCV000282762 uncertain significance Familial adenomatous polyposis 1 2018-11-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 1589 of the APC protein (p.Arg1589Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs72541813, ExAC 0.01%). This variant has been reported in an individual affected with multiple colorectal adenomas (PMID: 22773231). ClinVar contains an entry for this variant (Variation ID: 142201). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Counsyl RCV000232313 SCV000489580 uncertain significance Familial adenomatous polyposis 1 2016-10-26 criteria provided, single submitter clinical testing
Color RCV000131191 SCV000681683 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-11 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000211915 SCV000805412 uncertain significance not provided 2017-03-27 criteria provided, single submitter clinical testing
Mendelics RCV000232313 SCV000838121 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing

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