Submissions for variant NM_000038.6(APC):c.3289G>A (p.Glu1097Lys)

gnomAD frequency: 0.00001  dbSNP: rs1060503312

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004564085	SCV000552611	uncertain significance	Familial adenomatous polyposis 1	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1097 of the APC protein (p.Glu1097Lys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 411450). 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.
GeneDx	RCV000481132	SCV000570079	uncertain significance	not provided	2016-04-25	criteria provided, single submitter	clinical testing	This variant is denoted APC c.3289G>A at the cDNA level, p.Glu1097Lys (E1097K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Glu1097Lys 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 Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Glu1097Lys occurs at a position that is conserved across species and is located within the 15-amino acid repeat Beta-catenin 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 evidence, it is unclear whether APC Glu1097Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000569515	SCV000667652	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-21	criteria provided, single submitter	clinical testing	The p.E1097K variant (also known as c.3289G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 3289. The glutamic acid at codon 1097 is replaced by lysine, an amino acid with similar properties. This amino acid position is well 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.
Color Diagnostics, LLC DBA Color Health	RCV000569515	SCV001735448	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1097 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 hereditary cancer in the literature. This variant has been identified in 1/250290 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.