Submissions for variant NM_000038.6(APC):c.1535A>G (p.Asp512Gly)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004572161	SCV002591005	uncertain significance	Familial adenomatous polyposis 1	2025-01-27	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 512 of the APC protein (p.Asp512Gly). This variant is not present in population databases (gnomAD no frequency). 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: 1717854). 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	RCV002400429	SCV002706693	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-26	criteria provided, single submitter	clinical testing	The p.D512G variant (also known as c.1535A>G), located in coding exon 11 of the APC gene, results from an A to G substitution at nucleotide position 1535. The aspartic acid at codon 512 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. 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.
All of Us Research Program, National Institutes of Health	RCV004005601	SCV004832818	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 512 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 not been identified 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.