Submissions for variant NM_000038.6(APC):c.6865A>G (p.Thr2289Ala)

dbSNP: rs1554087807

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000581447	SCV000687098	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-21	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 2289 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 performed for this variant. This variant has not been reported in individuals affected with hereditary cancer 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.
Ambry Genetics	RCV000581447	SCV001187991	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-03	criteria provided, single submitter	clinical testing	The p.T2289A variant (also known as c.6865A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 6865. The threonine at codon 2289 is replaced by alanine, 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.
Invitae	RCV003653210	SCV001232584	uncertain significance	Familial adenomatous polyposis 1	2023-12-05	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 2289 of the APC protein (p.Thr2289Ala). This variant is not present in population databases (gnomAD no frequency). 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: 490346). 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.
GeneDx	RCV001550075	SCV001770350	uncertain significance	not provided	2021-02-03	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); 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
Sema4, Sema4	RCV000581447	SCV002526775	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-23	criteria provided, single submitter	curation