Submissions for variant NM_000038.6(APC):c.7099A>G (p.Thr2367Ala)

gnomAD frequency: 0.00004  dbSNP: rs772778630

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000692525	SCV000820352	uncertain significance	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2367 of the APC protein (p.Thr2367Ala). This variant is present in population databases (rs772778630, 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: 571390). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758740	SCV000887549	uncertain significance	not provided	2017-11-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000692525	SCV001136942	uncertain significance	Familial adenomatous polyposis 1	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001026031	SCV001188332	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-06	criteria provided, single submitter	clinical testing	The p.T2367A variant (also known as c.7099A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 7099. The threonine at codon 2367 is replaced by alanine, an amino acid with similar properties. This amino acid position is 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.
Color Diagnostics, LLC DBA Color Health	RCV001026031	SCV001352863	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-22	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 2367 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 breast and thyroid cancer (DOI: 10.1101/2021.04.15.21255554). This variant has been identified in 1/249654 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.
GeneDx	RCV000758740	SCV001777442	uncertain significance	not provided	2019-10-14	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
PreventionGenetics, part of Exact Sciences	RCV003420229	SCV004117873	uncertain significance	APC-related condition	2024-02-14	criteria provided, single submitter	clinical testing	The APC c.7099A>G variant is predicted to result in the amino acid substitution p.Thr2367Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. It is reported as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/571390/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000692525	SCV004203379	uncertain significance	Familial adenomatous polyposis 1	2023-07-21	criteria provided, single submitter	clinical testing