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

gnomAD frequency: 0.00001  dbSNP: rs200406572

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129389	SCV000184155	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-29	criteria provided, single submitter	clinical testing	The p.E2589G variant (also known as c.7766A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 7766. The glutamic acid at codon 2589 is replaced by glycine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV003650357	SCV000254039	uncertain significance	Familial adenomatous polyposis 1	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2589 of the APC protein (p.Glu2589Gly). This variant is present in population databases (rs200406572, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 41515). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. 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	2023-09-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with atherosclerosis undergoing exome sequencing (Johnston et al., 2012); This variant is associated with the following publications: (PMID: 18199528, 22703879)
Color Diagnostics, LLC DBA Color Health	RCV000129389	SCV000687142	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-03	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 2589 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 1/250812 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034400	SCV000888767	uncertain significance	not provided	2017-10-10	criteria provided, single submitter	clinical testing
Division of Medical Genetics, University of Washington	RCV000200515	SCV001424810	uncertain significance	Familial adenomatous polyposis 1	2019-06-17	criteria provided, single submitter	clinical testing	To our knowledge, this sequence variant has not been previously reported in the literature in individuals with colon polyps or colon cancer. This variant has an overall allele frequency of 0.000004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034400	SCV002010856	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000200515	SCV004196356	uncertain significance	Familial adenomatous polyposis 1	2023-10-16	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.