Submissions for variant NM_000038.6(APC):c.2645C>T (p.Thr882Ile)

gnomAD frequency: 0.00001  dbSNP: rs786203243

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166468	SCV000217265	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-26	criteria provided, single submitter	clinical testing	The p.T882I variant (also known as c.2645C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 2645. The threonine at codon 882 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not well 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.
Invitae	RCV003650431	SCV000552548	uncertain significance	Familial adenomatous polyposis 1	2023-07-30	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 882 of the APC protein (p.Thr882Ile). 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: 186817). 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. 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	RCV000166468	SCV001339396	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-15	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 882 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 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	RCV001775651	SCV002013835	uncertain significance	not provided	2022-04-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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
Baylor Genetics	RCV002515162	SCV004199621	uncertain significance	Familial adenomatous polyposis 1	2023-10-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995505	SCV004839707	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-02-24	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 882 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 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.