Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003328251 | SCV004035110 | likely pathogenic | CDH1-related diffuse gastric and lobular breast cancer syndrome | 2023-08-03 | reviewed by expert panel | curation | The c.1565+5G>A variant occurs in the splice donor region of intron 10. This variant is absent from population databases (PM2_supporting). The variant is predicted to result in loss of the canonical donor splice site and gain of a cryptic donor site at the +7 position by SpliceAI and VarSeak (PP3). RNA analysis has demonstrated a novel six base pair insertion (GTAAAT) resulting in a premature stop codon (p.Tyr523*) in carriers (PS3, internal data, SCV000214990.7). The c.1565+5G>A variant segregates with diffuse gastric cancer in one family meeting IGCLC criteria for HDGC (PS4_supporting and PP1, unpublished). In summary, this variant is classified as likely pathogenic based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PM2_supporting, PS3, PS4_supporting, PP3 and PP1. |
| Ambry Genetics | RCV000164357 | SCV000214990 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-01-10 | criteria provided, single submitter | clinical testing | The c.1565+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 10 in the CDH1 gene. This alteration has been detected in two individuals whose personal and/or family histories are consistent with CDH1-associated hereditary cancer syndrome (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP splice site prediction tool, this alteration is not predicted to have a significant impact on the native splice donor site. Using the ESEfinder splice site prediction tool, this alteration is predicted to impact the effectiveness of the native splice donor site. Using the Human Slicing Finder splice prediction tool, this alteration predicts a significant weakening in the native donor splice site efficiency (Desmet FO et al. Nucleic Acids Res. 2009 May;37(9):e67). RNA studies have demonstrated that this alteration results in 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. |
| Invitae | RCV000804323 | SCV000944227 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2019-01-13 | criteria provided, single submitter | clinical testing | 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. 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. This variant has not been reported in the literature in individuals with CDH1-related disease. ClinVar contains an entry for this variant (Variation ID: 185005). This variant is not present in population databases (ExAC 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, but it affects a nucleotide within the consensus splice site of the intron. |