ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2782G>A (p.Ala928Thr) (rs730881222)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159509 SCV000209464 uncertain significance not provided 2018-07-02 criteria provided, single submitter clinical testing This variant is denoted APC c.2782G>A at the cDNA level, p.Ala928Thr (A928T) at the protein level, and results in the change of an Alanine to a Threonine (GCC>ACC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. APC Ala928Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Ala928Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000814588 SCV000955001 uncertain significance Familial adenomatous polyposis 1 2018-10-03 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 928 of the APC protein (p.Ala928Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs730881222, 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: 181768). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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