ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2474dup (p.Pro826fs)

dbSNP: rs1555518221
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328412 SCV004035081 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-02 reviewed by expert panel curation The NM_004360.5:c.2474dup (p.Pro826AlafsTer3) variant in CDH1 is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay. However, this truncated region (removes last 57 amino acids of the protein) is critical to protein function and located upstream the most 3' well-characterized pathogenic variant c.2506G>T (pGlu836Ter) (PVS1_Strong, PM5_Supporting; PMID: 29798843, ClinVar Variation ID: 479504). This variant is absent in gnomAD 2.1.1 (PM2_Supporting). This variant has been reported in 5 families meeting HDGC criteria (PS4; NCI hereditary gastric study, Ambry, Invitae). In summary, this variant meets the criteria to be classified as pathogenic for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PVS1_Strong, PS4, PM2_Supporting, PM5_Supporting. (CDH1 VCEP specifications version 3.1; 5/6/2022)
Ambry Genetics RCV000574087 SCV000665400 pathogenic Hereditary cancer-predisposing syndrome 2024-04-30 criteria provided, single submitter clinical testing The c.2474dupC pathogenic mutation, located in coding exon 16 of the CDH1 gene, results from a duplication of C at nucleotide position 2474, causing a translational frameshift with a predicted alternate stop codon (p.P826Afs*3). This alteration occurs at the 3' terminus of theCDH1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 55 amino acids of the protein. However, premature stop codons are typically deleterious in nature and 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;141:117-28). This variant has been observed in multiple individuals with a personal and/or family history that is consistent with CDH1-associated disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp RCV000792226 SCV000931507 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-06-27 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: 481178). This premature translational stop signal has been observed in individual(s) with lobular breast cancer (PMID: 29798843). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro826Alafs*3) in the CDH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 57 amino acid(s) of the CDH1 protein.
GeneDx RCV001584376 SCV001820694 likely pathogenic not provided 2022-10-07 criteria provided, single submitter clinical testing Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 57 amino acids are lost and replaced with 2 incorrect amino acids (HGMD); Not observed in large population cohorts (gnomAD); Observed in an individual with lobular breast cancer (Krempely and Karam, 2018); This variant is associated with the following publications: (PMID: 20371349, 15235021, 22850631, 29798843)
Myriad Genetics, Inc. RCV000792226 SCV004044501 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-06-15 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

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