Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000706865 | SCV000835939 | likely pathogenic | Hereditary diffuse gastric adenocarcinoma | 2023-06-11 | criteria provided, single submitter | clinical testing | 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). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (External communication). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 582725). This variant has been observed in individual(s) with diffuse gastric and lobular breast cancers (Invitae; External communication). 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 12 of the CDH1 gene. It does not directly change the encoded amino acid sequence of the CDH1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. |
| Ambry Genetics | RCV001013769 | SCV001174396 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-12-15 | criteria provided, single submitter | clinical testing | The c.1936+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 12 in the CDH1 gene. This alteration has been detected in a family with clinical history consistent with hereditary diffuse gastric cancer (Ambry internal data). This nucleotide position is well conserved in available vertebrate species. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and internal RNA studies showed abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Department of Clinical Genetics, |
RCV000706865 | SCV005689636 | likely pathogenic | Hereditary diffuse gastric adenocarcinoma | 2025-02-04 | criteria provided, single submitter | clinical testing | PVS1 (RNA); PM2_SUP |