ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1476_1477del (p.Arg492fs)

dbSNP: rs876659208
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328286 SCV001244352 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-25 reviewed by expert panel curation The c.1476_1477delAG p.(Arg492Serfs) 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). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Moderate; PMID: 15235021, 22020549). 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_Moderate, PM5_Supporting.
Ambry Genetics RCV000213871 SCV000275404 pathogenic Hereditary cancer-predisposing syndrome 2023-04-17 criteria provided, single submitter clinical testing The c.1476_1477delAG pathogenic mutation, located in coding exon 10 of the CDH1 gene, results from a deletion of two nucleotides at nucleotide positions 1476 to 1477, causing a translational frameshift with a predicted alternate stop codon (p.R492Sfs*44). This alteration has been reported in a family meeting clinical diagnostic criteria for hereditary diffuse gastric cancer (Brooks-Wilson AR et al. J. Med. Genet. 2004 Jul;41(7):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 RCV000554611 SCV000637726 pathogenic Hereditary diffuse gastric adenocarcinoma 2024-01-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg492Serfs*44) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with gastric cancer (PMID: 15235021, 22020549). ClinVar contains an entry for this variant (Variation ID: 231528). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000657196 SCV000778922 pathogenic not provided 2022-04-03 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15235021, 26182300, 16527687, 19269290, 22020549, 17545690, 26072394, 20373070)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657196 SCV001134055 pathogenic not provided 2019-05-09 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Color Diagnostics, LLC DBA Color Health RCV000213871 SCV001349495 pathogenic Hereditary cancer-predisposing syndrome 2021-12-15 criteria provided, single submitter clinical testing This variant deletes 2 nucleotides in exon 10 of the CDH1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with diffuse gastric cancer (PMID: 15235021, 22020549). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000554611 SCV003926799 pathogenic Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing PVS1; PS4_Supporting; PM2 (PMID: 30311375)
Myriad Genetics, Inc. RCV000554611 SCV004043611 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-06-13 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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