Submissions for variant NM_004360.5(CDH1):c.687+1G>C

dbSNP: rs1567504977

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001181241	SCV001346341	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-09-30	criteria provided, single submitter	clinical testing	This variant causes a G>C nucleotide substitution at the +1 position of intron 5 of the CDH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice donor site (c.687+1G>A, c.687+1_687+2del) are considered to be disease-causing (ClinVar variation ID: 567608, 483268), suggesting that the reference sequence at this splice site is important for normal RNA splicing. Based on the available evidence, this variant is classified as Likely Pathogenic.
Ambry Genetics	RCV001181241	SCV002665625	pathogenic	Hereditary cancer-predisposing syndrome	2019-09-19	criteria provided, single submitter	clinical testing	The c.687+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 5 of the CDH1 gene. This pathogenic mutation has been detected in a family meeting clinical criteria for hereditary diffuse gastric cancer (Ambry internal data). 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 a disease-causing mutation.
Myriad Genetics, Inc.	RCV003316830	SCV004018323	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-03-20	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.
Invitae	RCV003316830	SCV004449119	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-04-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 921686). Disruption of this splice site has been observed in individuals with diffuse gastric cancer (PMID: 15235021; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 5 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).