ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2164+2T>C

gnomAD frequency: 0.00001  dbSNP: rs876661120
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328300 SCV001943364 uncertain significance CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-04 reviewed by expert panel curation The c.2164+2T>C variant is a canonical splice variant predicted to result in a premature stop codon but not predicted to undergo NMD (PVS1_Strong). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, this variant meets criteria to be classified as variant of uncertain significance based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1_Strong, PM2_Supporting.
GeneDx RCV000215849 SCV000279584 pathogenic not provided 2015-11-13 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.2164+2T>C or IVS13+2T>C and consists of a T>C nucleotide substitution at the +2 position of intron 13 of the CDH1 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. Based on the current evidence, we consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003512026 SCV004334753 pathogenic Hereditary diffuse gastric adenocarcinoma 2025-01-21 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 13 of the CDH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individuals with hereditary diffuse gastric cancer and/or lobular breast cancer (PMID: 23709761; internal data). ClinVar contains an entry for this variant (Variation ID: 234613). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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