ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5540C>T (p.Thr1847Met) (rs371686531)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000546681 SCV000647597 uncertain significance Familial adenomatous polyposis 1 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1847 of the APC protein (p.Thr1847Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs371686531, ExAC 0.03%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 470013). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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 RCV000562281 SCV000667685 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000562281 SCV000681749 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780847 SCV000918457 uncertain significance not specified 2018-05-21 criteria provided, single submitter clinical testing Variant summary: APC c.5540C>T (p.Thr1847Met) results in a non-conservative amino acid change located in the 5th APC repeat (IPR009223) of the encoded protein sequence; these short repeat regions bind beta-catenin [PMID: 9823329]. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 245820 control chromosomes. This frequency is not higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (1.2e-05 vs 7.1e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.5540C>T in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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