Submissions for variant NM_004360.5(CDH1):c.2296-2A>G

dbSNP: rs876660393

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328291	SCV001943367	likely pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-24	reviewed by expert panel	curation	The c.2296-2A>G variant is a canonical splice variant predicted to result in a truncated protein (PVS1_strong, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_moderate; SCV000760771.5). 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, PS4_moderate, PM2_supporting, PM5_Supporting.
Ambry Genetics	RCV000214820	SCV000277786	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-24	criteria provided, single submitter	clinical testing	The c.2296-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 15 in 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 will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Another alteration impacting the same acceptor site (c.2296-1G>A) has been seen in multiple patients meeting diagnostic 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.
Invitae	RCV000639202	SCV000760771	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-01-25	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: 233417). Disruption of this splice site has been observed in individuals with hereditary diffuse gastric cancer (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 14 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).
Color Diagnostics, LLC DBA Color Health	RCV000214820	SCV000914010	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-05-05	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 14 of the CDH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. 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). Loss of CDH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV000639202	SCV004043172	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-06-15	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. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data].