ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7916A>C (p.Glu2639Ala) (rs778376399)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486703 SCV000567473 uncertain significance not provided 2015-07-27 criteria provided, single submitter clinical testing This variant is denoted APC c.7916A>C at the cDNA level, p.Glu2639Ala (E2639A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Glu2639Ala 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 Glutamic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Glu2639Ala occurs at a position where amino acids with properties similar to Glutamic Acid are tolerated across species and is located in the EB1 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 information, it is unclear whether APC Glu2639Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000582053 SCV000687153 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-01 criteria provided, single submitter clinical testing
Invitae RCV000646495 SCV000768268 uncertain significance Familial adenomatous polyposis 1 2018-05-24 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 2639 of the APC protein (p.Glu2639Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs778376399, ExAC 0.003%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 419575). 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 tolerated, 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.
Mendelics RCV000646495 SCV000838158 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing

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