ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1811C>G (p.Ala604Gly) (rs370955311)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218469 SCV000278245 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000481347 SCV000565957 uncertain significance not provided 2015-03-19 criteria provided, single submitter clinical testing This variant is denoted APC c.1811C>G at the cDNA level, p.Ala604Gly (A604G) 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 Ala604Gly was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Alanine and Glycine share similar properties, this is considered a conservative amino acid substitution. APC Ala604Gly occurs at a position that is well conserved across species and is located within the armadillo region (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 Ala604Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000543016 SCV000647202 uncertain significance Familial adenomatous polyposis 1 2018-08-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 604 of the APC protein (p.Ala604Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs370955311, 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: 233794). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Color RCV000218469 SCV000686858 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-12 criteria provided, single submitter clinical testing

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