Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000550240 | SCV000647148 | likely pathogenic | Familial adenomatous polyposis 1 | 2018-10-02 | criteria provided, single submitter | clinical testing | This variant results in a copy number gain of the genomic region encompassing promoter 1A and exons 2-5 of the APC gene. The 5' boundary is likely confined to be between promoter 1B and promoter 1A. The 3' boundary is likely confined to intron 5 of the APC gene. While the exact position of this variant cannot be determined from this data, sub-genic copy number gains are generally in tandem (PMID: 25640679). This particular gain has not been reported in the literature in individuals with APC-related disease. However, similar copy number gains involving promoter 1A, and exons 2 and 2-8 have been observed in individuals with clinical features consistent with familial adenomatous polyposis (FAP) or attenuated FAP (Invitae). There are several predicted outcomes of this duplication on APC protein function. While APC expression may occur in the duplicated region containing promoter 1A, it is more likely to be expressed from the original region also containing promoter 1B, which has been shown to drive higher levels of APC expression (PMID: 21643010). Therefore, the duplicated copy likely results in an absent or disrupted protein product. Experimental studies have not been tested for this variant. 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. |
| Invitae | RCV001858057 | SCV002286529 | likely pathogenic | Familial adenomatous polyposis 1 | 2021-08-02 | criteria provided, single submitter | clinical testing | This variant results in a copy number gain of the genomic region encompassing promoter 1A and exon(s) 2-5 of the APC gene. The 5' boundary is likely confined to be between promoter 1B and promoter 1A. The 3' boundary is likely confined to intron 5 of the APC gene. While the exact position of this variant cannot be determined from this data, sub-genic copy number gains are generally in tandem (PMID: 25640679). A similar copy number variant has been observed in individual(s) with familial adenomatous polyposis (Invitae). While APC expression may occur in the duplicated region containing promoter 1A, it is more likely to be expressed from the original region also containing promoter 1B, which has been shown to drive higher levels of APC expression (PMID: 21643010). Therefore, the duplicated copy likely results in an absent or disrupted protein product. Experimental studies have not been tested for this variant. 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. |