ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1564A>G (p.Met522Val)

gnomAD frequency: 0.00001  dbSNP: rs587781692
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129857 SCV000184674 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-28 criteria provided, single submitter clinical testing The p.M522V variant (also known as c.1564A>G), located in coding exon 12 of the APC gene, results from an A to G substitution at nucleotide position 1564. The methionine at codon 522 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV002228650 SCV000552645 uncertain significance Familial adenomatous polyposis 1 2023-01-30 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 522 of the APC protein (p.Met522Val). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function. ClinVar contains an entry for this variant (Variation ID: 141366). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is present in population databases (rs587781692, gnomAD 0.006%).
Mendelics RCV000469283 SCV000838075 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000129857 SCV001339391 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-10 criteria provided, single submitter clinical testing This missense variant replaces methionine with valine at codon 522 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 2/250890 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV000469283 SCV004015203 uncertain significance Familial adenomatous polyposis 1 2023-07-07 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 522 of the APC protein (p.Met522Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. ClinVar contains 3 entries for this variant (Variation ID: 141366) all listed as variant of uncertain significance. 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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