Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000767181 | SCV000293795 | uncertain significance | not provided | 2016-01-05 | criteria provided, single submitter | clinical testing | This variant is denoted APC c.3325G>T at the cDNA level, p.Gly1109Cys (G1109C) at the protein level, and results in the change of a Glycine to a Cysteine (GGT>TGT). This variant was observed in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old, this the unaffected status of this individual may not be significant. APC Gly1109Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Gly1109Cys occurs at a position that is not conserved and is located in a B-catenin binding domain, a Serine-rich region, and a region responsible for down-regulation through a process mediated by direct ubiquitination (Azzopardi 2008, Uniprot). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether APC Gly1109Cys is pathogenic or benign. We consider it to be a variant of uncertain significance. |
| Invitae | RCV003534352 | SCV001237220 | uncertain significance | Familial adenomatous polyposis 1 | 2023-09-29 | 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: 133528). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 1109 of the APC protein (p.Gly1109Cys). |
| Ambry Genetics | RCV002453438 | SCV002611661 | uncertain significance | Hereditary cancer-predisposing syndrome | 2017-10-03 | criteria provided, single submitter | clinical testing | The p.G1109C variant (also known as c.3325G>T), located in coding exon 15 of the APC gene, results from a G to T substitution at nucleotide position 3325. The glycine at codon 1109 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS ONE, 2014 Apr;9:e94554). This amino acid position is not well 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. |
| ITMI | RCV000120038 | SCV000084170 | not provided | not specified | 2013-09-19 | no assertion provided | reference population |