Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000574350 | SCV000667470 | pathogenic | Hereditary cancer-predisposing syndrome | 2017-06-22 | criteria provided, single submitter | clinical testing | Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity |
| Invitae | RCV000805097 | SCV000945041 | pathogenic | Familial adenomatous polyposis 1 | 2018-08-31 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 6 of the APC gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with familial adenomatous polyposis (PMID: 17411426). ClinVar contains an entry for this variant (Variation ID: 482288). Experimental studies have shown that this missense change results in in-frame skipping of exon 6 (previously referred to as exon 5)(PMID: 22987206). A different variant affecting this nucleotide (c.645+1G>A) has been determined to be pathogenic (PMID: 8381580, 20685668, 17411426, Invitae). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Donor and acceptor splice site variants 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). For these reasons, this variant has been classified as Pathogenic. |