Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000347640 | SCV000329236 | likely pathogenic | not provided | 2024-04-02 | criteria provided, single submitter | clinical testing | In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge |
Labcorp Genetics |
RCV000700022 | SCV000828758 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2020-11-30 | 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: 279748). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 14 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV002298559 | SCV002598783 | uncertain significance | not specified | 2022-09-19 | criteria provided, single submitter | clinical testing | Variant summary: CDH1 c.2296-3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 3 prime acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251348 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of germline c.2296-3A>G in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
Ambry Genetics | RCV002450796 | SCV002737647 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-03-21 | criteria provided, single submitter | clinical testing | The c.2296-3A>G intronic variant results from an A to G substitution 3 nucleotides upstream from coding exon 15 in the CDH1 gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. 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. |
Myriad Genetics, |
RCV000700022 | SCV004043161 | likely pathogenic | Hereditary diffuse gastric adenocarcinoma | 2023-06-15 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. |