Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002230448 | SCV000552449 | pathogenic | Familial adenomatous polyposis 1 | 2023-08-07 | criteria provided, single submitter | clinical testing | This variant has been observed in individual(s) with familial adenomatous polyposis (FAP) and attenuated FAP (PMID: 15131404, 23159591). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 5 of the APC gene. It does not directly change the encoded amino acid sequence of the APC protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is also known as IVS4+2insT and c.531+2_531+3insT. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 5 (also known as exon 4 in the literature) and introduces a premature termination codon (PMID: 15131404). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 411336). |
| Ambry Genetics | RCV002348333 | SCV002644939 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-02-16 | criteria provided, single submitter | clinical testing | The c.531+2dupT intronic pathogenic mutation, results from a duplication of one nucleotide at the +2 position after coding exon 4 of the APC gene. This alteration has been observed in individuals with a personal and/or family history that is consistent with APC-related disease (Ambry internal data; Neklason DW et al. Fam. Cancer 2004 ; 3(1):35-40; Kerr SE et al. J Mol Diagn 2013 Jan; 15(1):31-43). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results a transcript which deletes exon 4 and is subject to nonsense-mediated decay (Ambry internal data; Neklason DW et al. Fam. Cancer 2004 ; 3(1):35-40). As such, this alteration is classified as pathogenic. |
| Myriad Genetics, |
RCV003335337 | SCV004043958 | pathogenic | Familial adenomatous polyposis 1 | 2023-04-27 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15131404]. |