ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6676C>G (p.Arg2226Gly) (rs1064794626)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484339 SCV000569602 uncertain significance not provided 2016-03-15 criteria provided, single submitter clinical testing This variant is denoted APC c.6676C>G at the cDNA level, p.Arg2226Gly (R2226G) at the protein level, and results in the change of an Arginine to a Glycine (CGA>GGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Arg2226Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Arg2226Gly occurs at a position that is conserved across species and is located within the basic domain (Azzopardi 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether APC Arg2226Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000543284 SCV000647660 uncertain significance Familial adenomatous polyposis 1 2017-06-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 2226 of the APC protein (p.Arg2226Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a APC-related disease. ClinVar contains an entry for this variant (Variation ID: 420672). 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: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on APC function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000562431 SCV000672597 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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