Submissions for variant NM_000038.6(APC):c.323G>A (p.Gly108Glu)

gnomAD frequency: 0.00001  dbSNP: rs1114167456

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000491472	SCV000579491	likely benign	Colorectal cancer, susceptibility to	2016-05-17	criteria provided, single submitter	clinical testing	The APC p.G108E, c.323 G>A variant did not segregate with colon cancer or polyposis in a single large family. Two individuals with no polyps did not have this APC variant and the majority of indivduals with multiple polyps or colon cancer did not have this variant. Based on this information, the likelihood that APC p.G108E is associated associated with polyposis is estimated to be less than one in one hundred.
Color Diagnostics, LLC DBA Color Health	RCV000775971	SCV000910486	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 108 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. This variant has not been identified 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.
Invitae	RCV002231614	SCV001216010	uncertain significance	Familial adenomatous polyposis 1	2023-08-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 108 of the APC protein (p.Gly108Glu). This variant is not present in population databases (gnomAD no frequency). 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: 427929). 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. 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.
Sema4, Sema4	RCV000775971	SCV002533182	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-27	criteria provided, single submitter	curation
Ambry Genetics	RCV000775971	SCV002611776	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-06	criteria provided, single submitter	clinical testing	The p.G108E variant (also known as c.323G>A), located in coding exon 3 of the APC gene, results from a G to A substitution at nucleotide position 323. The glycine at codon 108 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GenomeConnect - Invitae Patient Insights Network	RCV003483636	SCV004228684	not provided	Familial adenomatous polyposis 1; APC-related attenuated familial adenomatous polyposis		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 02-14-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.