ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2593C>G (p.Pro865Ala) (rs192620988)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159541 SCV000209503 uncertain significance not provided 2014-09-02 criteria provided, single submitter clinical testing This variant is denoted APC c.2593C>G at the cDNA level, p.Pro865Ala (P865A) at the protein level, and results in the change of a Proline to an Alanine (CCA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Pro865Ala 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 Proline and Alanine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Pro865Ala occurs at a position that is moderately conserved across species and is not located in a known functional domain (UniProt, 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 Pro865Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000702760 SCV000831628 uncertain significance Familial adenomatous polyposis 1 2018-06-01 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 865 of the APC protein (p.Pro865Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs192620988, 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: 181794). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; 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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