Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000222341 | SCV000275160 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-05-15 | criteria provided, single submitter | clinical testing | The c.531G>A variant (also known as p.Q177Q), located in coding exon 4 of the CDH1 gene, results from a G to A substitution at nucleotide position 531. This nucleotide substitution does not change the glutamine residue at codon 177. However, this change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish and weaken the native donor splice site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV000697324 | SCV000825926 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2018-02-14 | criteria provided, single submitter | clinical testing | This sequence change affects codon 177 of the CDH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CDH1 protein. This variant also falls at the last nucleotide of exon 4 of the CDH1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDH1-related disease. ClinVar contains an entry for this variant (Variation ID: 231342). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |