Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV002523975 | SCV003836599 | uncertain significance | Familial adenomatous polyposis 1 | 2023-02-25 | reviewed by expert panel | curation | The c.3083G>A variant in APC is a missense variant predicted to cause the substitution of serine to asparagine at amino acid position 1028 (p.Ser1028Asn). This alteration has been identified in 2 families with attenuated FAP worth 1 phenotype points (PS4_supporting). Two other missense variants (c.3084T>A and c.3083G>T) in the same codon leading to a different amino acid change at this position (p.Ser1028Arg; p.Ser1028Ile) have been classified as Likely Pathogenic by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (PM5_Supporting). Co-segregation data shows that this variant segregated with FAP in 6 meiosis in one family (PP1_Moderate; Ambry internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, due to insufficient evidence, this variant is a VUS for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis: PS4_Supporting, PM5_Supporting, PP1_Moderate and PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). |
| Ambry Genetics | RCV000491338 | SCV000579939 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-03-06 | criteria provided, single submitter | clinical testing | The p.S1028N pathogenic mutation (also known as c.3083G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 3083. The serine at codon 1028 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with APC-related disease (Ambry internal data; Personal communication). This alteration was shown to segregate with disease in one family (Ambry internal data). A nearby amino acid, APC p.N1026, likely interacts directly with APC p.S1028. A missense alteration at the nearby amino acid, APC p.N1026S, which was also shown to segregate with AFAP, is impaired in its ability to bind to β-Catenin and, thus, impaired in reducing β-Catenin signaling (Menéndez M et al. Gastroenterology. 2008 Jan;134:56-64; Kohler EM et al. Hum. Mol. Genet. 2008 Jul;17:1978-87). Internal structural analysis shows that this variant (p.S1028N) lies on the protein interface that is indicated to be important for β-Catenin binding (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Invitae | RCV002523975 | SCV001235085 | uncertain significance | Familial adenomatous polyposis 1 | 2023-04-15 | 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: 428186). 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 serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1028 of the APC protein (p.Ser1028Asn). |