Submissions for variant NM_000038.6(APC):c.7967A>G (p.Asp2656Gly)

dbSNP: rs1463203731

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587099	SCV000694129	uncertain significance	not provided	2017-02-09	criteria provided, single submitter	clinical testing	Variant summary: The APC c.7967A>G (p.Asp2656Gly) variant involves the alteration of a conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest has not been observed in large, broad control populations (ExAC, 1000 Gs, or ESP), nor has it been, to our knowledge, reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Labcorp Genetics (formerly Invitae), Labcorp	RCV002530881	SCV000768149	uncertain significance	Familial adenomatous polyposis 1	2024-07-22	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 2656 of the APC protein (p.Asp2656Gly). 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: 495374). 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.
Color Diagnostics, LLC DBA Color Health	RCV001185311	SCV001351498	uncertain significance	Hereditary cancer-predisposing syndrome	2025-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 2656 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 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.
Ambry Genetics	RCV001185311	SCV002677184	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-07	criteria provided, single submitter	clinical testing	The p.D2656G variant (also known as c.7967A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 7967. The aspartic acid at codon 2656 is replaced by glycine, an amino acid with similar properties. This amino acid position is highly 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.
Baylor Genetics	RCV002530881	SCV004205906	uncertain significance	Familial adenomatous polyposis 1	2023-05-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002391	SCV004835744	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 2656 of the APC protein. Computational prediction tool 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer 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.