ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1009_1010del (p.Ser337Phefs)

dbSNP: rs786201045
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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 RCV003328244 SCV001365412 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-25 reviewed by expert panel curation The c.1009_1010delAG (p.Ser337Phefs) 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://https://gnomad.broadinstitute.org/). Two probands meet HDGC phenotype criteria (PS4_Moderate; SCV000212776.4). 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 RCV000162429 SCV000212776 pathogenic Hereditary cancer-predisposing syndrome 2017-12-04 criteria provided, single submitter clinical testing The c.1009_1010delAG pathogenic mutation, located in coding exon 8 of the CDH1 gene, results from a deletion of two nucleotides at nucleotide positions 1009 to 1010, causing a translational frameshift with a predicted alternate stop codon (p.S337Ffs*12). This mutation has been reported in a cohort of French CDH1 mutation carriers (Benusiglio PR et al. J. Med. Genet. 2015 Aug;52:563-5). 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001195162 SCV002242982 pathogenic Hereditary diffuse gastric adenocarcinoma 2021-08-06 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with clinical features of hereditary diffuse gastric cancer and has been described as disease causing (PMID: 26182300). This variant is also known as c.1009-2delAG in the literature. ClinVar contains an entry for this variant (Variation ID: 183727). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser337Phefs*12) 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).
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV001195162 SCV003926720 pathogenic Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing PVS1; PS4_Moderate; PM2 (PMID: 30311375)
Myriad Genetics, Inc. RCV001195162 SCV004044251 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-06-12 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics RCV003462115 SCV004215733 pathogenic Familial cancer of breast 2023-05-15 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000162429 SCV004360464 pathogenic Hereditary cancer-predisposing syndrome 2023-07-17 criteria provided, single submitter clinical testing This variant deletes 2 nucleotides 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. This variant has been observed in an individual affected with lobular breast cancer before the age of 55 years (PMID: 36436516) and in an individual affected with gastric cancer at age 54 with a family history of the disease (PMID: doi:10.1007/s12672-023-00623-4). 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.
GenomeConnect - Invitae Patient Insights Network RCV001195162 SCV004228789 not provided Hereditary diffuse gastric adenocarcinoma no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 12-07-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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