ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6734C>T (p.Pro2245Leu)

gnomAD frequency: 0.00001  dbSNP: rs1483215684
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000773024 SCV000906406 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-24 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 2245 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/31368 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 RCV000773024 SCV001187809 uncertain significance Hereditary cancer-predisposing syndrome 2022-08-23 criteria provided, single submitter clinical testing The p.P2245L variant (also known as c.6734C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 6734. The proline at codon 2245 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV003744638 SCV002287264 uncertain significance Familial adenomatous polyposis 1 2023-01-30 criteria provided, single submitter clinical testing 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: 628541). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2245 of the APC protein (p.Pro2245Leu).

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