ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2594G>A (p.Trp865Ter)

dbSNP: rs1555518270
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328438 SCV001142258 uncertain significance CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-04 reviewed by expert panel curation The c.2594G>A p.(Trp865Ter) variant is predicted to result in a premature stop codon that leads to a truncated protein. However, it is located within the nonsense mediated decay resistance region and is downstream of the most 3' pathogenic variant, c.2506G>T p.(Glu836Ter), PVS1_Moderate. This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1_Moderate, PM2_Supporting.
Ambry Genetics RCV000597446 SCV000700321 uncertain significance Hereditary cancer-predisposing syndrome 2021-10-28 criteria provided, single submitter clinical testing The p.W865* variant (also known as c.2594G>A), located in coding exon 16 of the CDH1 gene, results from a G to A substitution at nucleotide position 2594. This changes the amino acid from a tryptophan to a stop codon within coding exon 16. This alteration occurs at the 3' terminus of theCDH1 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 2%, 18 amino acids, of the protein. The exact functional effect of this alteration is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000662745 SCV000785524 uncertain significance Hereditary diffuse gastric adenocarcinoma 2017-11-14 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000662745 SCV002227614 uncertain significance Hereditary diffuse gastric adenocarcinoma 2021-07-25 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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 conditions. ClinVar contains an entry for this variant (Variation ID: 496819). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the CDH1 gene (p.Trp865*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acids of the CDH1 protein.

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