Submissions for variant NM_004360.5(CDH1):c.1566-1G>C

gnomAD frequency: 0.00001  dbSNP: rs113583899

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328415	SCV001943358	uncertain significance	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-21	reviewed by expert panel	curation	The c.1566-1G>C 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 v2.1.1 cohort. In the gnomAD v3 it has a frequency of 0.000006978 (1 of 143,302) with a maximum non-founder allele frequency of 0.00001549 (1 of 64,570) in the European non-Finnish subpopulation (PM2_supporting; http://gnomad.broadinstitute.org). The variant has been reported in two families meeting clinical criteria for HDGC (PS4_moderate, SCV000666335.2, internal laboratory contributor). 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_moderate, PM2_supporting.
Ambry Genetics	RCV000567023	SCV000666335	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-05	criteria provided, single submitter	clinical testing	The c.1566-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 11 of the CDH1 gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 may result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000639263	SCV000760833	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 10 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 individual(s) with clinical features of CDH1-related condition (PMID: 34643667). ClinVar contains an entry for this variant (Variation ID: 481704). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002476224	SCV002774273	likely pathogenic	not provided	2021-07-16	criteria provided, single submitter	clinical testing	This variant is located in a canonical splice-acceptor site and is predicted to interfere with normal CDH1 mRNA splicing. To the best of our knowledge, the variant has not been reported in the published literature. Based on the available information, the variant is predicted to be likely pathogenic.
Myriad Genetics, Inc.	RCV000639263	SCV004045018	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.
Baylor Genetics	RCV003459325	SCV004215726	uncertain significance	Familial cancer of breast	2024-01-25	criteria provided, single submitter	clinical testing