ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4088A>T (p.Lys1363Ile) (rs373607243)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000474316 SCV000552643 uncertain significance Familial adenomatous polyposis 1 2018-10-20 criteria provided, single submitter clinical testing This sequence change replaces lysine with isoleucine at codon 1363 of the APC protein (p.Lys1363Ile). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and isoleucine. This variant is present in population databases (rs373607243, ExAC 0.01%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 411471). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000771584 SCV000904168 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-12 criteria provided, single submitter clinical testing

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