ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2240C>T (p.Ser747Leu) (rs773020689)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168160 SCV000218821 uncertain significance Familial adenomatous polyposis 1 2018-10-15 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 747 of the APC protein (p.Ser747Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs773020689, ExAC 0.009%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 188223). 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: "Probably Damaging"; 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.
Ambry Genetics RCV000218100 SCV000273931 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000484713 SCV000571474 uncertain significance not provided 2017-12-08 criteria provided, single submitter clinical testing This variant is denoted APC c.2240C>T at the cDNA level, p.Ser747Leu (S747L) at the protein level, and results in the change of a Serine to a Leucine (TCA>TTA). This variant has not, to our knowledge, been published in the literature as a germline variant; however it has been reported to occur in a prostate tumor sample (Hovelson 2015). APC Ser747Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Serine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Ser747Leu is located in the Armadillo region (Azzopardi 2008). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether APC Ser747Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000218100 SCV000681510 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-08 criteria provided, single submitter clinical testing

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