ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2490dup (p.Leu831fs)

dbSNP: rs1131690822
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328382 SCV001943349 likely pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-30 reviewed by expert panel curation The c.2490dupG (p.Leu831AlafsTer4) variant results in a premature stop codon that leads to a truncated protein. It is located within the nonsense mediated decay resistant zone, and upstream of codon 836 where the most 3' pathogenic variant in CDH1 terminates (PVS1_Strong, PMID: 29798843). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in a family meeting HDGC criteria (PS4_Supporting; SCV000580713.3). In summary, the clinical significance of this variant is likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, Supporting, PM2_Supporting
Ambry Genetics RCV000492088 SCV000580713 likely pathogenic Hereditary cancer-predisposing syndrome 2015-07-31 criteria provided, single submitter clinical testing The c.2490dupG variant, located in coding exon 16 of the CDH1 gene, results from a duplication of G at nucleotide position 2490, and causes a translational frameshift with a predicted alternate stop codon (p.L831Afs*4). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of CDH1, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 52 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time; however, the deleted region eliminates the catenin-binding domain, which is important for regulating the stability of cadherin mediated cell-cell adhesion (Ishiyama N et al. Cell 2010 Apr; 141(1):117-28). In addition, this alteration was previously seen in a patient diagnosed with diffuse gastric cancer at 31 (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV001712455 SCV003461741 pathogenic Hereditary diffuse gastric adenocarcinoma 2022-03-01 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CDH1 protein in which other variant(s) (p.Glu836*) have been determined to be pathogenic (PMID: 29798843). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 428634). This premature translational stop signal has been observed in individuals with diffuse gastric cancer (PMID: 29798843; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu831Alafs*4) in the CDH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 amino acid(s) of the CDH1 protein.

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