ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7766A>G (p.Glu2589Gly) (rs200406572)

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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 RCV000129389 SCV000184155 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000200515 SCV000254039 uncertain significance Familial adenomatous polyposis 1 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 2589 of the APC protein (p.Glu2589Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs200406572, ExAC 0.006%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 41515). 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: "Tolerated"; PolyPhen-2: "Probably 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.
GeneDx RCV000034400 SCV000565845 uncertain significance not provided 2017-02-09 criteria provided, single submitter clinical testing This variant is denoted APC c.7766A>G at the cDNA level, p.Glu2589Gly (E2589G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAA>GGA). This variant was observed in 1/560 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). APC Glu2589Gly 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 Glutamic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Glu2589Gly occurs at a position that is conserved in mammals and is located in the EB1 binding domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether APC Glu2589Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000129389 SCV000687142 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034400 SCV000888767 uncertain significance not provided 2017-10-10 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034400 SCV001154483 uncertain significance not provided 2018-05-01 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034400 SCV000043142 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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