Submissions for variant NM_000038.6(APC):c.6977G>A (p.Arg2326Gln)

gnomAD frequency: 0.00004  dbSNP: rs531178000

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129062	SCV000183763	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-13	criteria provided, single submitter	clinical testing	The p.R2326Q variant (also known as c.6977G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 6977. The arginine at codon 2326 is replaced by glutamine, an amino acid with highly 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.
GeneDx	RCV000480098	SCV000567817	uncertain significance	not provided	2021-02-23	criteria provided, single submitter	clinical testing	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV003325186	SCV000647682	uncertain significance	Familial adenomatous polyposis 1	2024-11-19	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 2326 of the APC protein (p.Arg2326Gln). This variant is present in population databases (rs531178000, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 29596542). ClinVar contains an entry for this variant (Variation ID: 140854). 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	RCV000129062	SCV000905995	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 2326 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 been reported in an individual affected with colorectal cancer in the literature (PMID: 29596542). This variant has been identified in 3/282010 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.
Sema4, Sema4	RCV000129062	SCV002526919	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-03	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271411	SCV002555651	uncertain significance	not specified	2022-06-06	criteria provided, single submitter	clinical testing	Variant summary: APC c.6977G>A (p.Arg2326Gln) results in a conservative amino acid change located in the adenomatous polyposis coli protein basic domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250628 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6977G>A in individuals affected with APC-related cancer syndromes and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003325186	SCV004031135	uncertain significance	Familial adenomatous polyposis 1	2023-08-17	criteria provided, single submitter	clinical testing	The APC c.6977G>A (p.Arg2326Gln) missense change has a maximum subpopulation frequency of 0.01% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in the literature in individuals with APC-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.?
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480098	SCV004220502	uncertain significance	not provided	2023-01-05	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00012 (3/24850 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003997477	SCV004843487	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-04-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 2326 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. 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 3/282010 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000480098	SCV002036045	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000480098	SCV002037311	uncertain significance	not provided		no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV001824638	SCV002074964	not provided	Familial adenomatous polyposis 1; Gastric adenocarcinoma and proximal polyposis of the stomach; APC-related attenuated familial adenomatous polyposis		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 02-04-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.