ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.603del (p.Val202fs)

dbSNP: rs1131690809
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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 RCV003328370 SCV001244354 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-25 reviewed by expert panel curation The c.603delT p.(Val202Leufs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000580694.3). 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.
Ambry Genetics RCV000492348 SCV000580694 pathogenic Hereditary cancer-predisposing syndrome 2022-12-19 criteria provided, single submitter clinical testing The c.603delT pathogenic mutation, located in coding exon 5 of the CDH1 gene, results from a deletion of one nucleotide at nucleotide position 603, causing a translational frameshift with a predicted alternate stop codon (p.V202Lfs*13). This pathogenic mutation has been reported in the literature in a cohort of French CDH1 carriers, but specific personal and family history information was not provided (Benusiglio PR et al. J. Med. Genet. 2015 Aug;52(8):563-5). 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.
GeneDx RCV000522621 SCV000618416 likely pathogenic not provided 2017-04-17 criteria provided, single submitter clinical testing This deletion of one nucleotide in CDH1 is denoted c.603delT at the cDNA level and p.Val202LeufsX13 (V202LfsX13) at the protein level. The normal sequence, with the base that is deleted in brackets, is ACCCCC[delT]GTTG. The deletion causes a frameshift which changes a Valine to a Leucine at codon 202, and creates a premature stop codon at position 13 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.603delT has been observed in a patient with a history suspicious for Hereditary Diffuse Gastric Cancer (Benusiglio 2015). Based on the currently available information, we consider this deletion to be a likely pathogenic variant.
Color Diagnostics, LLC DBA Color Health RCV000492348 SCV000911554 pathogenic Hereditary cancer-predisposing syndrome 2024-01-02 criteria provided, single submitter clinical testing This variant deletes 1 nucleotide in exon 5 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 hereditary diffuse gastric cancer (PMID: 26025002, 31077828). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001078227 SCV001339072 pathogenic Hereditary diffuse gastric adenocarcinoma 2020-03-13 criteria provided, single submitter clinical testing Variant summary: CDH1 c.603delT (p.Val202LeufsX13) 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. A truncation downstream of this position has been classified as pathogenic by our laboratory. The variant was absent in 251230 control chromosomes (gnomAD). c.603delT has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer (examples- Benusiglio_2015, Kumar_2020) and other cancer phenotypes (examples- Xicola_2019). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001078227 SCV001390571 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-12-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val202Leufs*13) 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 individual(s) with a history suspicious for hereditary diffuse gastric cancer (PMID: 26025002). ClinVar contains an entry for this variant (Variation ID: 428620). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc. RCV001078227 SCV004044614 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-06-09 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000522621 SCV004220841 pathogenic not provided 2023-01-04 criteria provided, single submitter clinical testing This frameshift variant alters the translational reading frame of the CDH1 mRNA and causes the premature termination of CDH1 protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with gastric cancer (PMID: 31077828 (2020)) and pancreatic cancer (PMID: 31296550 (2019)). The variant has also been reported in a large screening study of CDH1 mutation carriers (PMID: 26025002 (2015)). Based on the available information, this variant is classified as pathogenic.

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