Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000130298 | SCV000185147 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-08-11 | criteria provided, single submitter | clinical testing | The p.I1579V variant (also known as c.4735A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 4735. The isoleucine at codon 1579 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in patients whose clinical history is consistent with attenuated familial adenomatous polyposis (Ambry internal data). In one study, p.I1579V was detected in one individual with multiple colorectal adenomas (total number of adenomas unknown) and 0/969 unrelated healthy controls (Azzopardi D et al. Cancer Res. 2008 Jan 15;68(2):358-63). Overall, this study found a higher frequency of rare, non-synonymous changes in individuals with multiple adenomas. It has been suggested that this missense alteration within a SAMP-repeat region might disrupt APC secondary structure related to Axin binding (Minde DP et al. Mol Cancer. 2011 Aug 22;10:101). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV003534380 | SCV004292824 | uncertain significance | Familial adenomatous polyposis 1 | 2023-06-25 | 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: 141684). This missense change has been observed in individual(s) with colorectal adenomas (PMID: 18199528). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1579 of the APC protein (p.Ile1579Val). |