ClinVar Miner

Submissions for variant NM_000038.6(APC):c.54G>A (p.Met18Ile)

gnomAD frequency: 0.00002  dbSNP: rs772873692
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003766595 SCV000552742 uncertain significance Familial adenomatous polyposis 1 2024-01-27 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 18 of the APC protein (p.Met18Ile). This variant is present in population databases (rs772873692, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 411541). 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 with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health RCV000581033 SCV000681743 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-19 criteria provided, single submitter clinical testing This missense variant replaces methionine with isoleucine at codon 18 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 5/251302 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.
Ambry Genetics RCV000581033 SCV001186159 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-27 criteria provided, single submitter clinical testing The p.M18I variant (also known as c.54G>A), located in coding exon 1 of the APC gene, results from a G to A substitution at nucleotide position 54. The methionine at codon 18 is replaced by isoleucine, 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.

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