Submissions for variant NM_000038.6(APC):c.3674C>G (p.Ala1225Gly)

dbSNP: rs1554085218

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004568938	SCV000647465	uncertain significance	Familial adenomatous polyposis 1	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1225 of the APC protein (p.Ala1225Gly). 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: 469933). 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	RCV000774964	SCV000909056	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 1225 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 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.
Sema4, Sema4	RCV000774964	SCV002533891	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-06	criteria provided, single submitter	curation
Ambry Genetics	RCV000774964	SCV003874621	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-01	criteria provided, single submitter	clinical testing	The p.A1225G variant (also known as c.3674C>G), located in coding exon 15 of the APC gene, results from a C to G substitution at nucleotide position 3674. The alanine at codon 1225 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. Based on the available evidence, the clinical significance of this variant remains unclear.
All of Us Research Program, National Institutes of Health	RCV003999386	SCV004837827	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 1225 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 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.