ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5194A>G (p.Met1732Val) (rs752065261)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000338065 SCV000452021 uncertain significance APC-Associated Polyposis Disorders 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000467696 SCV000552648 uncertain significance Familial adenomatous polyposis 1 2018-04-28 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 1732 of the APC protein (p.Met1732Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs752065261, ExAC 0.002%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 350414). 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 RCV000482902 SCV000564575 uncertain significance not provided 2017-12-14 criteria provided, single submitter clinical testing This variant is denoted APC c.5194A>G at the cDNA level, p.Met1732Val (M1732V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Met1732Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. APC Met1732Val is located in a beta-catenin down-regulating domain and the SAMP repeats/axin binding domain (Azzopardi 2008). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Met1732Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000573682 SCV000667401 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000779704 SCV000916457 uncertain significance not specified 2017-12-04 criteria provided, single submitter clinical testing Variant summary: The APC c.5194A>G (p.Met1732Val) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/245306 control chromosomes at a frequency of 0.0000122, 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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