ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1948_1949dup (p.Ile651fs)

dbSNP: rs1555517074
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328395 SCV001943351 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-04 reviewed by expert panel curation The c.1948_1949dup p.(Ile651fs) 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000551453 SCV000637760 pathogenic Hereditary diffuse gastric adenocarcinoma 2017-04-06 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This sequence change inserts 2 nucleotide in exon 13 of the CDH1 mRNA (c.1948_1949dupAT), causing a frameshift at codon 651. This creates a premature translational stop signal (p.Ile651Serfs*3) and is expected to result in an absent or disrupted protein product.

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