Submissions for variant NM_000038.6(APC):c.3494A>T (p.Lys1165Ile)

dbSNP: rs765887499

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000775139	SCV000909259	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-05	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with isoleucine at codon 1165 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 been identified in 1/250556 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.
Invitae	RCV002535521	SCV002236088	uncertain significance	Familial adenomatous polyposis 1	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 1165 of the APC protein (p.Lys1165Ile). This variant is present in population databases (rs765887499, 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: 630118). 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.
Ambry Genetics	RCV000775139	SCV002615800	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-31	criteria provided, single submitter	clinical testing	The p.K1165I variant (also known as c.3494A>T), located in coding exon 15 of the APC gene, results from an A to T substitution at nucleotide position 3494. The lysine at codon 1165 is replaced by isoleucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV002473129	SCV002770200	uncertain significance	not provided	2022-12-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18199528)