Submissions for variant NM_000038.6(APC):c.1829A>G (p.Asp610Gly)

gnomAD frequency: 0.00001  dbSNP: rs756090401

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220561	SCV000274304	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-01	criteria provided, single submitter	clinical testing	The p.D610G variant (also known as c.1829A>G), located in coding exon 14 of the APC gene, results from an A to G substitution at nucleotide position 1829. The aspartic acid at codon 610 is replaced by glycine, an amino acid with similar properties. This amino acid position is well 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	RCV000220561	SCV000681489	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-27	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 610 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 been reported in individual affected with colorectal cancer or more than one colon polyps (PMID: 31422818). This variant has been identified in 3/282718 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000603089	SCV000712548	uncertain significance	not specified	2017-01-05	criteria provided, single submitter	clinical testing	The p.Asp610Gly variant in APC has not been previously reported in individuals w ith APC-associated polyposis. This variant has been identified in 1/8642 of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadi nstitute.org; dbSNP rs756090401). Computational prediction tools and conservatio n analysis do not provide strong support for or against an impact to the protein . In summary, the clinical significance of the p.Asp610Gly variant is uncertain.
Invitae	RCV003765406	SCV000818082	uncertain significance	Familial adenomatous polyposis 1	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 610 of the APC protein (p.Asp610Gly). This variant is present in population databases (rs756090401, gnomAD 0.005%). 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: 230672). 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 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002229549	SCV003843105	uncertain significance	Familial adenomatous polyposis 1	2023-03-14	criteria provided, single submitter	clinical testing	The APC c.1829A>G (p.Asp610Gly) missense change has a maximum subpopulation frequency of 0.0050% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with APC-related familial adenomatous polyposis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477724	SCV004221899	uncertain significance	not provided	2022-10-18	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported in individuals with APC-related conditions in the published literature. The frequency of this variant in the general population, 0.000011 (3/282718 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.