Submissions for variant NM_000038.6(APC):c.6547T>A (p.Ser2183Thr)

gnomAD frequency: 0.00001  dbSNP: rs764180204

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003534614	SCV000821205	uncertain significance	Familial adenomatous polyposis 1	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 2183 of the APC protein (p.Ser2183Thr). This variant is present in population databases (rs764180204, 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: 572047). 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	RCV001186452	SCV001352856	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-22	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 2183 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 performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/249112 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	RCV001186452	SCV002658979	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-01	criteria provided, single submitter	clinical testing	The p.S2183T variant (also known as c.6547T>A), located in coding exon 15 of the APC gene, results from a T to A substitution at nucleotide position 6547. The serine at codon 2183 is replaced by threonine, an amino acid with similar properties. This amino acid position is not 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	RCV002532234	SCV004195177	uncertain significance	Familial adenomatous polyposis 1	2023-10-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478420	SCV004219656	uncertain significance	not provided	2023-03-13	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, 0.000008 (2/249112 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV003983169	SCV004800424	uncertain significance	APC-related condition	2024-02-14	criteria provided, single submitter	clinical testing	The APC c.6547T>A variant is predicted to result in the amino acid substitution p.Ser2183Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/572047/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.