Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000129236 | SCV000183993 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-03-31 | criteria provided, single submitter | clinical testing | The p.S2260N variant (also known as c.6779G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 6779. The serine at codon 2260 is replaced by asparagine, an amino acid with highly similar properties. This alteration was identified in a cohort of triple-negative breast cancer patients undergoing multigene panel testing; the same patient also had the APC p.Ala740Pro (c.2218G>C) alteration (Lovejoy LA et al. Austin J Cancer Clin Res. 2018 Jun;5(1)). This amino acid position is highly conserved through mammals but not in all 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. |
| Invitae | RCV003467106 | SCV000260672 | uncertain significance | Familial adenomatous polyposis 1 | 2024-01-30 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 2260 of the APC protein (p.Ser2260Asn). This variant is present in population databases (rs587781393, gnomAD 0.004%). 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: 140955). 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. |
| Gene |
RCV000479990 | SCV000572068 | uncertain significance | not provided | 2023-02-28 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed with another APC variant (A740P) in an individual with personal and family history of breast cancer; however, it is unknown whether the two APC variants were on the same (in cis) or opposite (in trans) allele (Lovejoy et al., 2018); This variant is associated with the following publications: (PMID: 25256751, 18199528, Lovejoy2018) |
| Color Diagnostics, |
RCV000129236 | SCV000687094 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-23 | criteria provided, single submitter | clinical testing | This missense variant replaces serine with asparagine at codon 2260 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 3/282380 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. |
| Baylor Genetics | RCV003467106 | SCV004197553 | uncertain significance | Familial adenomatous polyposis 1 | 2023-10-27 | criteria provided, single submitter | clinical testing |