Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV002537180 | SCV003836619 | likely pathogenic | Familial adenomatous polyposis 1 | 2023-02-19 | reviewed by expert panel | curation | The c.1626G>C variant in APC is a G to non-G change at the last nucleotide of exon 13. It is predicted to cause skipping of exon 13, resulting in an in-frame deletion of an exon with sufficient supportive clinical data (r.1549_1626del) (p.A517_Q542del) (PVS1_Strong). This prediction is confirmed by RT-PCR analysis (supplanted by PVS1_Strong; PMID 24599579). This variant was detected in one proband and two other family members, the combined phenotypic point is 1 (PS4_Supporting). Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant is classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PVS1_Strong, PS4_Supporting and PM2_Supporting. (VCEP specifications version 1; date of approval: 12/12/2022). |
| Labcorp Genetics |
RCV002537180 | SCV000944483 | likely pathogenic | Familial adenomatous polyposis 1 | 2019-03-18 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine with histidine at codon 542 of the APC protein (p.Gln542His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 13 of the APC coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with clinical features of familial adenomatous polyposis (FAP) in a family (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant results in skipping of exon 13 (also known as exon 12 in the literature) (PMID: 24599579). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |