ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.781G>T (p.Glu261Ter)

dbSNP: rs121964873
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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 RCV003328150 SCV001142249 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-04 reviewed by expert panel curation The c.781G>T (p.Glu261Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, 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 (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting.
Invitae RCV000991090 SCV002147714 pathogenic Hereditary diffuse gastric adenocarcinoma 2021-04-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu261*) 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 (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with lobular breast cancer (PMID: 9744472). ClinVar contains an entry for this variant (Variation ID: 12234).
Ambry Genetics RCV002408458 SCV002673353 pathogenic Hereditary cancer-predisposing syndrome 2020-09-09 criteria provided, single submitter clinical testing The p.E261* pathogenic mutation (also known as c.781G>T), located in coding exon 6 of the CDH1 gene, results from a G to T substitution at nucleotide position 781. This changes the amino acid from a glutamic acid to a stop codon within coding exon 6. This alteration was previously detected in a patient with lobular breast cancer (Berx G et al. EMBO J., 1995 Dec;14:6107-15). 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.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000991090 SCV003926688 pathogenic Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing PVS1; PS4_Moderate; PM2 (PMID: 30311375)
OMIM RCV000013021 SCV000033266 pathogenic Breast lobular carcinoma 1995-12-15 no assertion criteria provided literature only
Laboratory for Genotyping Development, RIKEN RCV003162242 SCV002758156 pathogenic Gastric cancer 2021-07-01 no assertion criteria provided research

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