ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1064del (p.Gly354_Leu355insTer)

dbSNP: rs1555515731
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328276 SCV001244353 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-25 reviewed by expert panel curation The c.1064delT p.(Leu355Terfs) 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_Supporting; PMID: 16061854). 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000196464 SCV000253885 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-06-23 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 224528). This variant is also known as c.1063del. This premature translational stop signal has been observed in individual(s) with gastric, stomach, and bladder cancer (PMID: 16061854, 26845104). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu355*) 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).
University of Washington Department of Laboratory Medicine, University of Washington RCV000210107 SCV000266061 pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000210107 SCV000580692 pathogenic Hereditary cancer-predisposing syndrome 2021-06-03 criteria provided, single submitter clinical testing The c.1064delT pathogenic mutation, located in coding exon 8 of the CDH1 gene, results from a deletion of one nucleotide at nucleotide position 1064, causing a translational frameshift with a predicted alternate stop codon (p.L355*). This mutation, designated as c.1063del, has been previously reported in an individual diagnosed with diffuse gastric cancer at 27 years of age (Suriano G et al. Clin. Cancer Res., 2005 Aug;11:5401-9). 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.
CSER _CC_NCGL, University of Washington RCV000196464 SCV000700108 pathogenic Hereditary diffuse gastric adenocarcinoma 2016-10-01 criteria provided, single submitter research Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 32 year old male with gastric cancer, bladder cancer and colon polyps. Family history of gastric cancer and colon polyps. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Color Diagnostics, LLC DBA Color Health RCV000210107 SCV000904988 pathogenic Hereditary cancer-predisposing syndrome 2020-05-04 criteria provided, single submitter clinical testing This variant deletes 1 nucleotide in exon 8 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with diffused gastric cancer (PMID: 16061854) and another individual affected with stomach cancer described as a single focal tumor (PMID: 19269290). 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.
Myriad Genetics, Inc. RCV000196464 SCV004044456 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-06-12 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

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