Submissions for variant NM_000038.6(APC):c.8401C>T (p.Arg2801Trp)

gnomAD frequency: 0.00001  dbSNP: rs1242407699

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000567866	SCV000667520	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	The p.R2801W variant (also known as c.8401C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 8401. The arginine at codon 2801 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004561667	SCV000832672	uncertain significance	Familial adenomatous polyposis 1	2024-11-04	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 2801 of the APC protein (p.Arg2801Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 482321). 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	RCV000567866	SCV000904371	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 2801 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 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.
GeneDx	RCV001591331	SCV001823528	uncertain significance	not provided	2019-11-04	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001591331	SCV004220665	uncertain significance	not provided	2023-09-14	criteria provided, single submitter	clinical testing	To the best of our knowledge, this variant has not been reported in individuals affected with familial adenomatous polyposis (FAP) in the published literature. The frequency of this variant in the general population, 0.000011 (3/268772 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.
All of Us Research Program, National Institutes of Health	RCV004000968	SCV004835806	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-06-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 2801 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 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.
Baylor Genetics	RCV004561667	SCV005056453	uncertain significance	Familial adenomatous polyposis 1	2023-12-20	criteria provided, single submitter	clinical testing