ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5741C>G (p.Ala1914Gly) (rs199904481)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235260 SCV000293888 uncertain significance not provided 2018-10-11 criteria provided, single submitter clinical testing This variant is denoted APC c.5741C>G at the cDNA level, p.Ala1914Gly (A1914G) at the protein level, and results in the change of an Alanine to a Glycine (GCA>GGA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. APC Ala1914Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the 20-amino acid repeat beta-catenin down-regulating domain, as well as the SAMP repeat/axin binding domain (Azzopardi 2008). 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 Ala1914Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000567524 SCV000667500 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000567524 SCV000909605 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-18 criteria provided, single submitter clinical testing
Invitae RCV000794978 SCV000934416 uncertain significance Familial adenomatous polyposis 1 2018-12-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 1914 of the APC protein (p.Ala1914Gly). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs199904481, ExAC 0.002%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 246367). 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.

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