ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2430del (p.Phe810fs) (rs786203752)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV000204049 SCV000864602 pathogenic Hereditary diffuse gastric cancer 2018-11-21 reviewed by expert panel curation The c.2430delT (p.Phe810Leufs*6) variant is predicted to result in a premature stop codon that leads to a truncated protein. However, it is located within the nonsense mediated decay resistance region upstream of c.2506G>T (p.Glu836*) (PVS1_Strong). This variant is absent in the gnomAD cohort (PM2; This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID 26182300, SCV000261293.4, SCV000218032.4). 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: PVS1_Strong, PM2, PS4.
Ambry Genetics RCV000167195 SCV000218032 pathogenic Hereditary cancer-predisposing syndrome 2019-03-21 criteria provided, single submitter clinical testing The c.2430delT pathogenic mutation, located in coding exon 15 of the CDH1 gene, results from a deletion of one nucleotide at nucleotide position 2430, causing a translational frameshift with a predicted alternate stop codon (p.F810Lfs*6). This alteration was identified in a proband with a family history of gastric cancer who was diagnosed with diffuse gastric cancer at age 45 (Hansford S et al. JAMA Oncol. 2015 Apr;1(1):23-32). In addition, a mutation resulting in the same stop codon (c.2398delC) has been seen in multiple patients and families with diffuse gastric cancer and lobular breast cancer (Kaurah P et al. JAMA. 2007 Jun;297(21):2360-72; Petridis C et al. Br. J. Cancer. 2014 Feb;110(4):1053-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000204049 SCV000261293 pathogenic Hereditary diffuse gastric cancer 2020-07-27 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the CDH1 gene (p.Phe810Leufs*6). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acids of the CDH1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in at least three families affected with diffuse gastric cancer and gastric cancer (PMID: 26182300, Invitae). ClinVar contains an entry for this variant (Variation ID: 187464). This truncating variant is expected to delete the C-terminal portion of the cytoplasmic domain of the CDH1 (E-cadherin) protein, which includes the binding domains for the PIP5K1C (phosphatidylinositol phosphate kinase, type I gamma) and CTNNB1 (beta-catenin) proteins (PMID: 22850631). Loss of these domains is expected to disrupt normal E-cadherin function. This suggests that deletion of this region of the CDH1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000484305 SCV000567126 pathogenic not provided 2018-04-30 criteria provided, single submitter clinical testing This deletion of one nucleotide in CDH1 is denoted c.2430delT at the cDNA level and p.Phe810LeufsX6 (F810LfsX6) at the protein level. The normal sequence, with the base that is deleted in brackets, is ATTT[delT]ATTG. The deletion causes a frameshift, which changes a Phenylalanine to a Leucine at codon 810, and creates a premature stop codon at position 6 of the new reading frame. This variant has been reported in a family with a diagnosis of Hereditary Diffuse Gastric Cancer (Hansford 2015). We consider this variant to be pathogenic.
Color Health, Inc RCV000167195 SCV000903747 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000204049 SCV000917127 likely pathogenic Hereditary diffuse gastric cancer 2018-02-16 criteria provided, single submitter clinical testing Variant summary: CDH1 c.2430delT (p.Phe810LeufsX6) 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. The variant was absent in 120568 control chromosomes. c.2430delT has been reported in the literature in at least one individual affected with Diffuse Gastric Cancer. 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. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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