ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3415A>C (p.Lys1139Gln) (rs201550951)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586988 SCV000209514 uncertain significance not provided 2018-08-14 criteria provided, single submitter clinical testing This variant is denoted APC c.3415A>C at the cDNA level, p.Lys1139Gln (K1139Q) at the protein level, and results in the change of a Lysine to a Glutamine (AAG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Lys1139Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Lysine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Lys1139Gln is located in the 15-amino acid Beta-catenin 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 Lys1139Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000159549 SCV000217820 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000228025 SCV000282741 uncertain significance Familial adenomatous polyposis 1 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamine at codon 1139 of the APC protein (p.Lys1139Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine. This variant is present in population databases (rs201550951, 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: 181801). 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000211910 SCV000591140 uncertain significance not specified 2012-04-20 criteria provided, single submitter clinical testing
Color RCV000159549 SCV000681598 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586988 SCV000694032 uncertain significance not provided 2017-02-23 criteria provided, single submitter clinical testing Variant summary: The APC c.3415A>C (p.Lys1139Gln) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 6/120724 control chromosomes at a frequency of 0.0000497, which does not exceed the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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