Submissions for variant NM_000038.6(APC):c.1868G>A (p.Arg623Gln)

gnomAD frequency: 0.00001  dbSNP: rs765557332

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000565584	SCV000675939	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-28	criteria provided, single submitter	clinical testing	The p.R623Q variant (also known as c.1868G>A), located in coding exon 14 of the APC gene, results from a G to A substitution at nucleotide position 1868. The arginine at codon 623 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly 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.
Color Diagnostics, LLC DBA Color Health	RCV000565584	SCV000686864	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 623 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 hereditary cancer in the literature. This variant has been identified in 1/31408 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.
Invitae	RCV003537207	SCV000942928	uncertain significance	Familial adenomatous polyposis 1	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 623 of the APC protein (p.Arg623Gln). This variant is present in population databases (rs765557332, gnomAD 0.007%). 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: 486784). 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.
GeneDx	RCV002307551	SCV002601241	uncertain significance	not provided	2022-11-08	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28481359, 11768390, 18199528)