Submissions for variant NM_000038.6(APC):c.3689A>G (p.Gln1230Arg)

gnomAD frequency: 0.00002  dbSNP: rs764706774

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003651971	SCV000647466	uncertain significance	Familial adenomatous polyposis 1	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 1230 of the APC protein (p.Gln1230Arg). This variant is present in population databases (rs764706774, gnomAD 0.003%). 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: 469934). 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	RCV000775140	SCV000909262	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-25	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 1230 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 been reported in an individual affected with breast cancer (PMID: 29684080). This variant has been identified in 4/249958 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.
Ambry Genetics	RCV000775140	SCV001182424	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-03	criteria provided, single submitter	clinical testing	The p.Q1230R variant (also known as c.3689A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 3689. The glutamine at codon 1230 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in one of 3476 patients from the The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV001332124	SCV001524334	uncertain significance	Desmoid disease, hereditary	2019-03-13	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genetic Services Laboratory, University of Chicago	RCV001821561	SCV002070002	uncertain significance	not specified	2019-12-23	criteria provided, single submitter	clinical testing	DNA sequence analysis of the APC gene demonstrated a sequence change, c.3689A>G, in exon 16 that results in an amino acid change, p.Gln1230Arg. This sequence change does not appear to have been previously described in patients with APC-related disorders and has been described in the gnomAD database with a low population frequency of 0.0016% (dbSNP rs764706774). The p.Gln1230Arg change affects a highly conserved amino acid residue located in a domain of the APC protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gln1230Arg substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gln1230Arg change remains unknown at this time.
GeneDx	RCV002289766	SCV002578820	uncertain significance	not provided	2022-10-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25186627, 29684080)
Baylor Genetics	RCV002528506	SCV004198868	uncertain significance	Familial adenomatous polyposis 1	2023-10-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002289766	SCV004222576	uncertain significance	not provided	2023-01-11	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000027 (3/112548 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with breast cancer (PMID: 25186627 (2018)). 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.