Submissions for variant NM_000038.6(APC):c.4088A>T (p.Lys1363Ile)

dbSNP: rs373607243

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003535734	SCV000552643	uncertain significance	Familial adenomatous polyposis 1	2024-01-13	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 1363 of the APC protein (p.Lys1363Ile). This variant is present in population databases (rs373607243, 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: 411471). 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	RCV000485843	SCV000564573	uncertain significance	not provided	2015-01-27	criteria provided, single submitter	clinical testing	This variant is denoted APC c.4088A>T at the cDNA level, p.Lys1363Ile (K1363I) at the protein level, and results in the change of a Lysine to an Isoleucine (AAA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Lys1363Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Lys1363Ile occurs at a position that is highly conserved across species and is located within the beta-catenin down-regulating domain (Azzopardi 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether APC Lys1363Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl	RCV000474316	SCV000785453	uncertain significance	Familial adenomatous polyposis 1	2017-08-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771584	SCV000904168	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-19	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with isoleucine at codon 1363 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 hereditary cancer in the literature. This variant has been identified in 1/245522 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	RCV000771584	SCV001183504	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-07	criteria provided, single submitter	clinical testing	The p.K1363I variant (also known as c.4088A>T), located in coding exon 15 of the APC gene, results from an A to T substitution at nucleotide position 4088. The lysine at codon 1363 is replaced by isoleucine, an amino acid with dissimilar properties. In one study, this alteration was not observed in 691 North American patients with colorectal adenomas, but was observed in 1/969 matched healthy controls (Azzopardi D et al. Cancer Res. 2008 Jan; 68(2):358-63). 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.
Sema4, Sema4	RCV000771584	SCV002531838	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-12	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485843	SCV002774419	uncertain significance	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000474316	SCV004018241	uncertain significance	Familial adenomatous polyposis 1	2023-02-14	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
PreventionGenetics, part of Exact Sciences	RCV003409636	SCV004109385	uncertain significance	APC-related condition	2023-08-08	criteria provided, single submitter	clinical testing	The APC c.4088A>T variant is predicted to result in the amino acid substitution p.Lys1363Ile. To our knowledge, this variant has not been reported to be associated with disease in the literature nor is it present in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In one study, this variant was detected in a healthy control subject (Azzopardi et al. 2008. PubMed ID: 18199528). In ClinVar, this variant is classified as a variant of uncertain significance by several laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/411471/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000474316	SCV004191595	uncertain significance	Familial adenomatous polyposis 1	2023-09-05	criteria provided, single submitter	clinical testing