Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003742787 | SCV000647716 | uncertain significance | Familial adenomatous polyposis 1 | 2020-03-10 | criteria provided, single submitter | clinical testing | In summary, this variant is a rare missense change with uncertain impact on 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. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is present in population databases (rs372535376, ExAC 0.004%) but has not been reported in the literature in individuals with an APC-related disease. This sequence change replaces glutamine with glutamic acid at codon 2500 of the APC protein (p.Gln2500Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. |
| Laboratory for Molecular Medicine, |
RCV000603962 | SCV000712634 | uncertain significance | not specified | 2016-11-25 | criteria provided, single submitter | clinical testing | The p.Gln2500Glu variant in APC has not been previously reported in individuals with APC-associated cancer, but has been identified in 3/112058 European chromos omes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.or g; dbSNP rs372535376). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summar y, the clinical significance of the p.Gln2500Glu variant is uncertain. |
| Color Diagnostics, |
RCV001190626 | SCV001358150 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-08-04 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamine with glutamic acid at codon 2500 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251280 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 | RCV001190626 | SCV002668928 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-04-17 | criteria provided, single submitter | clinical testing | The p.Q2500E variant (also known as c.7498C>G), located in coding exon 15 of the APC gene, results from a C to G substitution at nucleotide position 7498. The glutamine at codon 2500 is replaced by glutamic acid, an amino acid with highly similar properties. In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). 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. |