ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.382del (p.His128fs) (rs1555514492)

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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 RCV000576815 SCV000864604 pathogenic Hereditary diffuse gastric cancer 2018-11-21 reviewed by expert panel curation The c.382delC (p.His128Ilefs*87) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1). The variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). 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: PVS1, PM2, PS4_Supporting.
Ambry Genetics RCV000571499 SCV000675986 pathogenic Hereditary cancer-predisposing syndrome 2017-12-14 criteria provided, single submitter clinical testing The c.382delC pathogenic mutation, located in coding exon 3 of the CDH1 gene, results from a deletion of one nucleotide at nucleotide position 382, causing a translational frameshift with a predicted alternate stop codon (p.H128Ifs*87). This mutation has been identified in multiple individuals with gastric cancer and a family history of HDGC (Brooks-Wilson AR. J. Med. Genet. 2004 Jul; 41(7):508-17; Oliveira C. Gastroenterology. 2009 Jun; 136(7):2137-48). 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.
Counsyl RCV000576815 SCV000677781 pathogenic Hereditary diffuse gastric cancer 2017-01-13 criteria provided, single submitter clinical testing
Invitae RCV000576815 SCV000760844 pathogenic Hereditary diffuse gastric cancer 2017-12-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.His128Ilefs*87) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individual affected with diffuse gastric cancer (PMID: 15235021). Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000576815 SCV000919108 likely pathogenic Hereditary diffuse gastric cancer 2018-05-18 criteria provided, single submitter clinical testing Variant summary: CDH1 c.382delC (p.His128IlefsX87) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.2064_2065delTG, p.Cys688fsX1). The variant allele was found at a frequency of 1.2e-05 in 245470 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer (1.2e-05 vs 2.8e-05), allowing no conclusion about variant significance. The variant, c.382delC, has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer (Brooks-Wilson_2004, Oliveira_2009, Hansford_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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