Submissions for variant NM_000038.6(APC):c.3136A>G (p.Asn1046Asp)

gnomAD frequency: 0.00001  dbSNP: rs755493779

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003765276	SCV000254004	uncertain significance	Familial adenomatous polyposis 1	2023-04-22	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 216158). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is present in population databases (rs755493779, gnomAD 0.002%). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 1046 of the APC protein (p.Asn1046Asp).
GeneDx	RCV000236840	SCV000293452	uncertain significance	not provided	2017-01-27	criteria provided, single submitter	clinical testing	This variant is denoted APC c.3136A>G at the cDNA level, p.Asn1046Asp (N1046D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Asn1046Asp 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 Asparagine and Aspartic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. APC Asn1046Asp occurs at a position that is conserved in mammals and is located in the 15-aa 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 Asn1046Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000776353	SCV000911734	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-19	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 1046 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 2/250724 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.
Ambry Genetics	RCV000776353	SCV001180055	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-17	criteria provided, single submitter	clinical testing	The p.N1046D variant (also known as c.3136A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 3136. The asparagine at codon 1046 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is well 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000776353	SCV004228019	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-14	criteria provided, single submitter	clinical testing