ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1779dup (p.Ile594fs)

dbSNP: rs876661118
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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 RCV003328299 SCV001437622 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-25 reviewed by expert panel curation The c.1779dup p.(Ile594fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). Additionally, this variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 15235021). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting.
GeneDx RCV000222914 SCV000279577 pathogenic not provided 2016-01-18 criteria provided, single submitter clinical testing This duplication of one nucleotide in CDH1 is denoted c.1779dupC at the cDNA level and p.Ile594HisfsX11 (I594HfsX11) at the protein level. The normal sequence, with the base that is duplicated in braces, is GCCCC[C]ATAC. The duplication causes a frameshift, which changes an Isoleucine to a Histidine at codon 594, and creates a premature stop codon at position 11 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. CDH1 c.1779dupC has been observed in an individual with a personal and family history of diffuse gastric cancer (Brooks-Wilson 2004). Based on the currently available information, we consider this duplication to be pathogenic
Ambry Genetics RCV000492623 SCV000580712 pathogenic Hereditary cancer-predisposing syndrome 2022-06-16 criteria provided, single submitter clinical testing The c.1779dupC pathogenic mutation, located in coding exon 12 of the CDH1 gene, results from a duplication of C at nucleotide position 1779, causing a translational frameshift with a predicted alternate stop codon (p.I594Hfs*11). This mutation has been previously described in an individual with diffuse gastric cancer who also had a family history of diffuse gastric cancer (Brooks-Wilson AR et al. J. Med. Genet. 2004 Jul;41:508-17). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp RCV001260578 SCV003442009 pathogenic Hereditary diffuse gastric adenocarcinoma 2022-07-30 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 234610). This variant is also known as 1779insC. This premature translational stop signal has been observed in individual(s) with diffuse gastric cancer (PMID: 15235021). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile594Hisfs*11) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070).
Myriad Genetics, Inc. RCV001260578 SCV004043723 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-06-14 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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