Submissions for variant NM_004360.5(CDH1):c.1566-2A>G

dbSNP: rs1555516520

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328393	SCV001943357	uncertain significance	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-21	reviewed by expert panel	curation	The c.1566-2A>G variant is a canonical splice variant predicted to result in the use of a cryptic splice site which preserves the reading frame (PVS1_moderate). This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in one individual meeting criteria for HDGC (PS4_supporting; PMID: 31841163). In summary, the clinical significance of this variant is classified as of uncertain significance based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_moderate, PS4_supporting, PM2_supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547207	SCV000637734	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2017-03-13	criteria provided, single submitter	clinical testing	In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547), and loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic. This variant has not been reported in the literature in individuals with a CDH1-related disease. This sequence change affects an acceptor splice site in intron 10 of the CDH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Ambry Genetics	RCV002404426	SCV002709926	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-12-21	criteria provided, single submitter	clinical testing	The c.1566-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 11 in the CDH1 gene. This alteration has been reported in an individual who was found to have two foci of signet ring cell carcinoma on total gastrectomy; however they had no significant family history of hereditary diffuse gastric cancer and multiple additional individuals over the age of 50 were found to be positive for this variant but did not have gastric cancer (Katona BW et al. J. Natl. Cancer Inst., 2020 Apr;112:330-334). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel in-frame splice acceptor site. RNA studies have demonstrated both in-frame and out-of-frame abnormal splicing in the set of samples tested; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). Based on this data, this variant is classified as likely pathogenic; however it may not result in classic hereditary diffuse gastric cancer syndrome based on the limited data available. As risk estimates are unknown at this time, clinical correlation is advised.
Myriad Genetics, Inc.	RCV000547207	SCV004045142	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-06-14	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.