ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2287G>T (p.Glu763Ter) (rs587780787)

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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 RCV000123245 SCV001365447 pathogenic Hereditary diffuse gastric cancer 2020-05-31 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). It is absent in the gnomAD cohort (PM2; 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: PVS1, PM2, PS4_Supporting.
Invitae RCV000123245 SCV000166551 pathogenic Hereditary diffuse gastric cancer 2020-07-14 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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in families with hereditary diffuse gastric cancer (PMID: 15138207, 23752020, 20373070). ClinVar contains an entry for this variant (Variation ID: 136065). Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000223099 SCV000279391 pathogenic not provided 2018-09-07 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.2287G>T at the cDNA level and p.Glu763Ter (E763X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with diffuse gastric cancer (Charlton 2004, Guilford 2010, Li 2013), as well as breast cancer (Desmond 2015), and is considered pathogenic.
Ambry Genetics RCV000568475 SCV000665144 pathogenic Hereditary cancer-predisposing syndrome 2019-02-23 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<span style="color:rgb(84, 84, 84); font-family:roboto,arial,sans-serif; font-size:small">)<span style="color:rgb(84, 84, 84); font-family:roboto,arial,sans-serif; font-size:small"> 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 Health, Inc RCV000568475 SCV000689506 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000123245 SCV000698381 likely pathogenic Hereditary diffuse gastric cancer 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.

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