Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000588727 | SCV000694093 | likely pathogenic | Familial multiple polyposis syndrome | 2016-08-08 | criteria provided, single submitter | clinical testing | Variant summary: The APC c.646-2A>G variant involves the alteration of a conserved splice site nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant abolishes a normal splice site. This variant has been reported in at least one FAP patient and one hepatocellular carcinoma sample, and is absent in 112706 control chromosomes. Taken together, this variant is classified as likely pathogenic. |
Invitae | RCV003538393 | SCV002317306 | likely pathogenic | Familial adenomatous polyposis 1 | 2021-02-06 | criteria provided, single submitter | clinical testing | Disruption of this splice site has been observed in individual(s) with clinical features of familial adenomatous polyposis (PMID: 20685668, 12702169). ClinVar contains an entry for this variant (Variation ID: 495370). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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. |
MGZ Medical Genetics Center | RCV002289884 | SCV002580163 | likely pathogenic | Familial adenomatous polyposis 1 | 2021-09-07 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002367986 | SCV002659674 | pathogenic | Hereditary cancer-predisposing syndrome | 2017-01-30 | criteria provided, single submitter | clinical testing | The c.646-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 6 in the APC gene. This alteration was previously identified in a French cohort of patients with FAP (Lagarde A et al. J. Med. Genet. 2010 Oct;47:721-2). 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. As such, this alteration is classified as a disease-causing mutation. |
Myriad Genetics, |
RCV002530879 | SCV004044023 | 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. |