Submissions for variant NM_000038.6(APC):c.1867C>T (p.Arg623Trp)

gnomAD frequency: 0.00001  dbSNP: rs730881238

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000581316	SCV000209497	uncertain significance	not provided	2021-04-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26286987)
Labcorp Genetics (formerly Invitae), Labcorp	RCV004562318	SCV000552475	uncertain significance	Familial adenomatous polyposis 1	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 623 of the APC protein (p.Arg623Trp). This variant is present in population databases (rs730881238, gnomAD 0.006%). 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: 181790). 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.
Color Diagnostics, LLC DBA Color Health	RCV000772640	SCV000905883	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan 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 APC-related disorders in the literature. This variant has been identified in 3/251354 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	RCV000772640	SCV001174038	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	The p.R623W variant (also known as c.1867C>T), located in coding exon 14 of the APC gene, results from a C to T substitution at nucleotide position 1867. The arginine at codon 623 is replaced by tryptophan, an amino acid with dissimilar 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.
All of Us Research Program, National Institutes of Health	RCV003998406	SCV004839621	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 623 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 hereditary cancer in the literature. This variant has been identified in 3/251354 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000581316	SCV005622908	uncertain significance	not provided	2024-09-09	criteria provided, single submitter	clinical testing	The APC c.1867C>T (p.Arg623Trp) variant has not been reported in individuals with APC-related conditions in the published literature. The frequency of this variant in the general population, 0.000012 (3/251354 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.