Submissions for variant NM_004360.5(CDH1):c.531+1G>A

dbSNP: rs1131690808

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328368	SCV001142260	likely pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-24	reviewed by expert panel	curation	The c.531+1G>A variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two family meeting HDGC clinical criteria (PS4_moderate; SCV000580690.3; SCV000637838.2). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_strong, PM2_Supporting, PS4_moderate, PM5_Supporting.
Ambry Genetics	RCV000492098	SCV000580690	pathogenic	Hereditary cancer-predisposing syndrome	2020-05-29	criteria provided, single submitter	clinical testing	The c.531+1G>A pathogenic intronic variant results from a G to A substitution one nucleotide after coding exon 4 of the CDH1 gene. This alteration has been detected in a family meeting clinical criteria for hereditary diffuse gastric cancer (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000559451	SCV000637838	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2017-12-15	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 of the CDH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDH1-related disease. ClinVar contains an entry for this variant (Variation ID: 428618). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants 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). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000559451	SCV003933754	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-05-11	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.531+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251178 control chromosomes (gnomAD). c.531+1G>A has been reported in the literature in an individual affected with diffuse gastric cancer and signet cell colorectal cancer who had a family history of gastric and breast cancer (Adib_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34949788). Three submitters, including an expert panel (ClinGen CDH1 Variant Curation Expert Panel), have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=1)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV000559451	SCV004044939	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-06-09	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.