Submissions for variant NM_000038.6(APC):c.4709A>G (p.Asp1570Gly)

gnomAD frequency: 0.00002  dbSNP: rs373419559

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115095	SCV000149004	uncertain significance	not provided	2018-03-30	criteria provided, single submitter	clinical testing	This variant is denoted APC c.4709A>G at the cDNA level, p.Asp1570Gly (D1570G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Asp1570Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the 20-amino acid repeat beta-catenin down-regulating domain and SAMP repeats/axin binding domain (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether APC Asp1570Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV002228230	SCV000647533	uncertain significance	Familial adenomatous polyposis 1	2023-11-09	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 1570 of the APC protein (p.Asp1570Gly). This variant is present in population databases (rs373419559, gnomAD 0.002%). 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: 127297). 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.
Ambry Genetics	RCV000575957	SCV000667430	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-19	criteria provided, single submitter	clinical testing	The p.D1570G variant (also known as c.4709A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 4709. The aspartic acid at codon 1570 is replaced by glycine, 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	RCV000575957	SCV001344291	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-07	criteria provided, single submitter	clinical testing	This missense variant replaces Aspartic acid with Glycine at codon 1570 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 been identified in 2/250746 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.
PreventionGenetics, part of Exact Sciences	RCV003935095	SCV004753729	uncertain significance	APC-related condition	2023-12-04	criteria provided, single submitter	clinical testing	The APC c.4709A>G variant is predicted to result in the amino acid substitution p.Asp1570Gly. To our knowledge, this variant has not been reported in the literature in individuals with APC-related disorders. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD, and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127297/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.