ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6452C>T (p.Thr2151Ile) (rs1060503293)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467796 SCV000552559 uncertain significance Familial adenomatous polyposis 1 2016-10-27 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 2151 of the APC protein (p.Thr2151Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a APC-related disease. 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 C15"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000485592 SCV000569960 uncertain significance not specified 2017-03-27 criteria provided, single submitter clinical testing This variant is denoted APC c.6452C>T at the cDNA level, p.Thr2151Ile (T2151I) 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 Thr2151Ile 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 Thr2151Ile occurs at a position that is conserved in mammals and is located in a modified phosphothreonine residue (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether APC Thr2151Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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