Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000574350 | SCV000667470 | pathogenic | Hereditary cancer-predisposing syndrome | 2018-09-08 | criteria provided, single submitter | clinical testing | The c.645+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 5 of the APC gene. This alteration has been reported in multiple individuals with a personal and/or family history of FAP (Ambry internal data; Stekrova J et al. BMC Med. Genet. 2007; 8:16). RNA analysis reportedly reflected skipping of exon 5 which is an in frame event (Schwarzová L. Fam. Cancer. 2013 Mar;12(1):35-42.), and RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Additionally, an alteration at the same position, c.645+1G>A, was identified in 1 of 160 unrelated patients with FAP and was also shown to co-segregate with disease in the family (Olschwang S et al. Am. J. Hum. Genet. 1993 Feb; 52(2):273-9). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Invitae | RCV003537117 | SCV000945041 | pathogenic | Familial adenomatous polyposis 1 | 2022-10-13 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This sequence change affects a donor splice site in intron 6 of the APC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with familial adenomatous polyposis (PMID: 17411426, 20685668; Invitae). ClinVar contains an entry for this variant (Variation ID: 482288). For these reasons, this variant has been classified as Pathogenic. |
| Myriad Genetics, |
RCV002528043 | SCV004045730 | likely pathogenic | Familial adenomatous polyposis 1 | 2023-04-27 | criteria provided, single submitter | clinical testing | This variant is considered likely 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. |
| Baylor Genetics | RCV002528043 | SCV004205471 | pathogenic | Familial adenomatous polyposis 1 | 2023-06-06 | criteria provided, single submitter | clinical testing |