ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2287G>T (p.Glu763Ter)

dbSNP: rs587780787
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328195 SCV001365447 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-25 reviewed by expert panel curation The c.2287G>T (p.Glu763Ter) variant results in a premature translational stop signal within the NMD competent region (PVS1, PM5_Supporting). It is absent in the gnomAD cohort (PM2_Supporting; http://https://gnomad.broadinstitute.org/). The variant has been reported in a family meeting HDGC criteria (PMID: 20373070), an individual with signet ring cell carcinoma diagnosed at 33 years of age (PMID: 15138207), and four individuals with DGC (2 <40 years, 2 > 40 years; PMID: 29589180). These reports are mostly out of New Zealand and it is unclear if the reported individuals are all part of a larger kindred (PS4_Supporting). 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.
Invitae RCV000123245 SCV000166551 pathogenic Hereditary diffuse gastric adenocarcinoma 2024-01-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu763*) 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 hereditary diffuse gastric cancer (PMID: 15138207, 20373070, 23752020). ClinVar contains an entry for this variant (Variation ID: 136065). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000223099 SCV000279391 pathogenic not provided 2023-08-04 criteria provided, single submitter clinical testing Nonsense 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; Observed in individuals with CDH1-related phenotypes referred for genetic testing at GeneDx and in published literature (Charlton et al., 2004; Guilford et al., 2010; Li et al., 2013; Desmond et al., 2015; Hakkaart et al., 2019; Green et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22225527, 16527687, 22098830, 20373070, 24424122, 23752020, 23575477, 25525159, 26270727, 20371349, 28702897, 30977389, 30745422, 36063148, 33809393, 15138207, 34949788, 36246616, 26182300, 29589180)
Ambry Genetics RCV000568475 SCV000665144 pathogenic Hereditary cancer-predisposing syndrome 2023-02-08 criteria provided, single submitter clinical testing The p.E763* pathogenic mutation (also known as c.2287G>T), located in coding exon 14 of the CDH1 gene, results from a G to T substitution at nucleotide position 2287. This changes the amino acid from a glutamic acid to a stop codon within coding exon 14. This mutation has been reported in one individual with signet ring cell carcinoma of the stomach who was reportedly from a hereditary diffuse gastric cancer (HDGC) kindred (Charlton A et al. Gut. 2004 Jun;53(6):814-20). In a case study, this alteration was reported in two siblings, aged 38 and 32, with a strong family history of gastric cancer over at least 2 generations, including an aunt also testing positive for this mutation (Li J et al. Surg. Laparosc. Endosc. Percutan. Tech. 2013 Jun;23:e124-6). This mutation has also been reported in a cohort of 1046 individuals who were appropriate candidates for hereditary breast and ovarian cancer syndrome (HBOC) evaluation and who lacked BRCA1/2 mutations (Desmond A et al. JAMA Oncol. 2015 Oct;1:943-51). 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.
Color Diagnostics, LLC DBA Color Health RCV000568475 SCV000689506 pathogenic Hereditary cancer-predisposing syndrome 2022-08-01 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 14 of the CDH1 gene, creating a 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 and lobular breast cancer in the literature (PMID: 15138207, 23575477, 29589180). 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 RCV000123245 SCV000698381 likely pathogenic Hereditary diffuse gastric adenocarcinoma 2015-11-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000223099 SCV001134076 pathogenic not provided 2019-01-04 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, 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.
Myriad Genetics, Inc. RCV000123245 SCV004043931 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-06-15 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.
Baylor Genetics RCV003474740 SCV004210570 pathogenic Familial cancer of breast 2021-12-25 criteria provided, single submitter clinical testing

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