Submissions for variant NM_004360.5(CDH1):c.2295+3G>A

dbSNP: rs786203544

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166902	SCV000217720	uncertain significance	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	The c.2295+3G>A intronic variant results from a G to A substitution 3 nucleotides after coding exon 14 in the CDH1 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6498 samples (12996 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 45,000 alleles tested) in our clinical cohort. This nucleotide position is not well conserved in available vertebrate species, and A is the reference nucleotide in multiple species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this donor splice site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of c.2295+3G>A remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003624405	SCV004518782	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-04-26	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 187198). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 14 of the CDH1 gene. It does not directly change the encoded amino acid sequence of the CDH1 protein. It affects a nucleotide within the consensus splice site.
Myriad Genetics, Inc.	RCV003624405	SCV005407244	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-09-23	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing.