Total submissions: 5
| 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. |
| Labcorp Genetics |
RCV002528043 | SCV000945041 | pathogenic | Familial adenomatous polyposis 1 | 2022-10-13 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 482288). Disruption of this splice site has been observed in individuals with familial adenomatous polyposis (PMID: 17411426, 20685668; Invitae). This variant is not present in population databases (gnomAD no frequency). 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). |
| 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 | |
| Fulgent Genetics, |
RCV005034136 | SCV005667810 | likely pathogenic | Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach | 2024-05-21 | criteria provided, single submitter | clinical testing |