ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2780C>G (p.Ala927Gly) (rs587781500)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129473 SCV000184243 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000203976 SCV000259601 uncertain significance Familial adenomatous polyposis 1 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 927 of the APC protein (p.Ala927Gly). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs587781500, ExAC 0.006%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 141108). 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: "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.
GeneDx RCV000483264 SCV000566009 uncertain significance not provided 2018-02-19 criteria provided, single submitter clinical testing This variant is denoted APC c.2780C>G at the cDNA level, p.Ala927Gly (A927G) at the protein level, and results in the change of an Alanine to a Glycine (GCT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Ala927Gly 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 information, it is unclear whether APC Ala927Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000129473 SCV000686912 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
GeneKor MSA RCV000129473 SCV000821811 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779714 SCV000916469 uncertain significance not specified 2018-04-16 criteria provided, single submitter clinical testing Variant summary: APC c.2780C>G (p.Ala927Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 245756 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (2e-05 vs 7.1e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2780C>G in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.

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