ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.387+2T>A

dbSNP: rs903144020
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001021328 SCV001182930 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-26 criteria provided, single submitter clinical testing The c.387+2T>A intronic variant results from a T to A substitution two nucleotides after coding exon 3 in the CDH1 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in multiple in-frame splicing events of unknown functional significance (Ambry internal data). Another alteration at this same splice donor site, c.387+1G>A, is also predicted by in silico models to disrupt splicing. Internal RNA studies demonstrated that the c.387+1G>A variant similarly results in multiple in-frame splicing events of unknown functional significance (Ambry internal data). In addition, the c.387+2T>A alteration has been identified in individuals that do not have a personal or family history suggestive of hereditary diffuse gastric cancer (Ambry internal data). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV001063454 SCV001228301 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-11-22 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the CDH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 53 or insertion of 19 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer. However, it has not been observed in individuals with hereditary diffuse gastric cancer (PMID: 31206626; Invitae). ClinVar contains an entry for this variant (Variation ID: 824323). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in intron 3 and exon 2 (Poster G20 in http://jmd.amjpathol.org/article/S1525-1578(16)30178-7/pdf). 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.
Color Diagnostics, LLC DBA Color Health RCV001021328 SCV001341371 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-02 criteria provided, single submitter clinical testing

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