ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4898C>T (p.Thr1633Ile) (rs765215625)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485896 SCV000571915 uncertain significance not provided 2016-10-06 criteria provided, single submitter clinical testing This variant is denoted APC c.4898C>T at the cDNA level, p.Thr1633Ile (T1633I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Thr1633Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Thr1633Ile occurs at a position that is not conserved and is located in the 20aa repeat B-catenin down-regulating domain as well as the SAMP repeats/axin binding domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC Thr1633Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000685771 SCV000813268 uncertain significance Familial adenomatous polyposis 1 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1633 of the APC protein (p.Thr1633Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs765215625, ExAC 0.001%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 422439). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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