Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000490872 | SCV000579895 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2018-03-19 | criteria provided, single submitter | clinical testing | The c.1743G>C variant (also known as p.K581N), located in coding exon 13 of the APC gene, results from a G to C substitution at nucleotide position 1743. The lysine at codon 581 is replaced by asparagine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 13, which makes it likely to have some effect on normal mRNA splicing. An adjacent alteration at the penultimate nucleotide position of coding exon 13 (c.1742A>G) is a well-described mutation seen in a family with attenuated FAP that has been shown by functional mRNA studies to lead to aberrant splicing and in-frame skipping of coding exon 13 (Kaufmann A et al. J Mol Diagn. 2009 Mar; 11(2):131-9). Using the BDGP splice site prediction tool, c.1743G>C is predicted to result in a weakening of the native splice donor site, and using the ESEfinder splice site prediction tool, c.1743G>C is predicted to result in abolishment of the native splice donor site; however, direct evidence is unavailable. Of note, ESEfinder and BDGP are predicting a stronger impact on splicing for c.1743G>C as compared to c.1742A>G. This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV003651936 | SCV001224984 | likely pathogenic | Familial adenomatous polyposis 1 | 2022-02-20 | criteria provided, single submitter | clinical testing | This missense change has been observed in individuals with familial adenomatous polyposis (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 581 of the APC protein (p.Lys581Asn). This variant also falls at the last nucleotide of exon 14, which is part of the consensus splice site for this exon. ClinVar contains an entry for this variant (Variation ID: 428153). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). |
| Gene |
RCV001775830 | SCV002013119 | likely pathogenic | not provided | 2022-03-15 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20223039, 18199528, 19196998) |