ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.261del (p.Arg87fs)

dbSNP: rs1555514429
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328399 SCV001244357 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-04 reviewed by expert panel curation The c.261delG p.(Arg87Serfs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, 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 (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting.
Invitae RCV000532595 SCV000637813 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-12-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg87Serfs*30) 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 variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 463772). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV003302821 SCV004007959 pathogenic Hereditary cancer-predisposing syndrome 2023-04-03 criteria provided, single submitter clinical testing The c.261delG pathogenic mutation, located in coding exon 3 of the CDH1 gene, results from a deletion of one nucleotide at nucleotide position 261, causing a translational frameshift with a predicted alternate stop codon (p.R87Sfs*30). This alteration was identified in multiple individuals diagnosed with lobular breast cancer (Ambry internal data; Gamble LA et al. JAMA Surg, 2022 Jan;157:18-22). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Myriad Genetics, Inc. RCV000532595 SCV004043426 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-06-08 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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