Submissions for variant NM_000038.6(APC):c.2105G>A (p.Gly702Glu)

gnomAD frequency: 0.00001  dbSNP: rs876658289

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216688	SCV000273324	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-21	criteria provided, single submitter	clinical testing	The p.G702E variant (also known as c.2105G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 2105. The glycine at codon 702 is replaced by glutamic acid, 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.
Color Diagnostics, LLC DBA Color Health	RCV000216688	SCV000686876	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-15	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 702 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 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	RCV003743646	SCV000768024	uncertain significance	Familial adenomatous polyposis 1	2023-09-11	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 702 of the APC protein (p.Gly702Glu). 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: 229944). 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.
Counsyl	RCV000646256	SCV000785618	uncertain significance	Familial adenomatous polyposis 1	2017-10-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000216688	SCV002532289	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-05	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003316197	SCV004019722	uncertain significance	Familial adenomatous polyposis 1	2023-02-15	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000646256	SCV004204108	uncertain significance	Familial adenomatous polyposis 1	2023-05-10	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000503730	SCV000591107	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Gly702Glu variant was not identified in the literature, nor was it identified in any of the following databases: dbSNP, Exome Variant Server ESP Project, HGMD, UMD, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, “MMR Gene Unclassified Variants Database”. The p.Gly702 residue is conserved across mammals, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the p.Gly702Glu variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.