Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000532475 | SCV000637733 | pathogenic | Hereditary diffuse gastric adenocarcinoma | 2023-09-21 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24389957). ClinVar contains an entry for this variant (Variation ID: 463722). This variant has been observed in individuals with diffuse gastric cancer (PMID: 24389957; 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 falls in intron 10 of the CDH1 gene. It does not directly change the encoded amino acid sequence of the CDH1 protein. It affects a nucleotide within the consensus splice site. |
| Ambry Genetics | RCV000567317 | SCV000675991 | pathogenic | Hereditary cancer-predisposing syndrome | 2016-09-28 | criteria provided, single submitter | clinical testing | The c.1565+2_1565+3insTT intronic pathogenic mutation results from the insertion of two nucleotides (TT) at positions c.1565+2 to c.1565+3, which is two nucleotides after coding exon 10 of the CDH1 gene. This mutation was reported in a large Danish family with gastric cancer and a history suggesting HDGC (Bardram L et al. Fam. Cancer, 2014 Jun;13:231-42). Bardram et al. further assessed the functional significance of this alteration using a mini-gene assay and showed this alteration results in a deletion of exon 10. Authors also note that seven asymptomatic mutation carriers underwent prophylactic gastrectomy and small foci of diffuse gastric cancer were found in all patients. Based on the available evidence, c.1565+2_1565+3insTT is classified as a pathogenic mutation. |
| Color Diagnostics, |
RCV000567317 | SCV000903634 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-05-05 | criteria provided, single submitter | clinical testing | This variant causes the insertion of two nucleotides in intron 10 splice donor site of the CDH1 gene. This variant is also known as c.1565+3insTT in the literature. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing, and an RNA mini-gene study showed that the variant resulted in two aberrant splicing products predicted to create absent or non-functional protein product (PMID: 24389957). This variant has been reported in diffuse gastric cancer affected individuals from two families (PMID: 24389957, 31296550), and it has been shown that this variant segregates with disease in multiple affected members in one of the two families (PMID: 24389957). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |
| Center for Genomic Medicine, |
RCV002268147 | SCV002551776 | pathogenic | not provided | 2023-08-15 | criteria provided, single submitter | clinical testing | |
| Institute for Biomarker Research, |
RCV000567317 | SCV004228172 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-10-31 | criteria provided, single submitter | clinical testing |