Submissions for variant NM_000038.6(APC):c.5177A>G (p.Glu1726Gly)

gnomAD frequency: 0.00001  dbSNP: rs587780598

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122785	SCV000166042	uncertain significance	Familial adenomatous polyposis 1	2024-10-21	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 1726 of the APC protein (p.Glu1726Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 135707). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV000575009	SCV000675875	uncertain significance	Hereditary cancer-predisposing syndrome	2025-01-13	criteria provided, single submitter	clinical testing	The p.E1726G variant (also known as c.5177A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 5177. The glutamic acid at codon 1726 is replaced by glycine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000122785	SCV000784827	uncertain significance	Familial adenomatous polyposis 1	2016-12-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000575009	SCV001353120	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-08	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 1726 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 been identified in 1/245182 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.
Myriad Genetics, Inc.	RCV000122785	SCV004018783	uncertain significance	Familial adenomatous polyposis 1	2023-02-21	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.
All of Us Research Program, National Institutes of Health	RCV003997380	SCV004838011	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 1726 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 been identified in 1/245182 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354105	SCV001548636	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The APC p.Glu1726Gly variant was not identified in the literature nor was it identified in the LOVD 3.0 or UMD-LSDB databases. The variant was identified in dbSNP (rs587780598) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and Counsyl). The variant was identified in control databases in 2 of 281,834 chromosomes at a frequency of 0.000007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 2 of 19,946 chromosomes (freq: 0.0001); it was not observed in the African, Latino, Ashkenazi Jewish, Finnish, European, Other or South Asian populations. The p.Glu1726 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Gly variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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 uncertain significance.