Submissions for variant NM_004360.5(CDH1):c.1008G>A (p.Glu336=)

dbSNP: rs267606712

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328287	SCV000864616	likely pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-28	reviewed by expert panel	curation	The c.1008G>A p.(Glu336=) variant results in a G to non-G change at the last nucleotide of an exon (PVS1_Moderate). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is also an RNA assay demonstrating abnormal out-of-frame transcript (PS3; PMID: 18427545). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Moderate, PM2_Supporting, PS3.
Ambry Genetics	RCV000217412	SCV000275557	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	clinical testing	The c.1008G>A pathogenic mutation (also known as p.E336E), located in coding exon 7 of the CDH1 gene, results from a G to A substitution at nucleotide position 1008. This nucleotide substitution does not change the amino acid at codon 336. However, this change occurs in the last base pair of coding exon 7, which makes it likely to have some effect on normal mRNA splicing. This alteration was previously identified in a patient with diffuse gastric cancer (Ambry internal data). It was also observed in a gastric cancer cell line originating from a patient with diffuse gastric cancer (Oda T et al. Proc. Natl. Acad. Sci. U.S.A. 1994 Mar; 91(5):1858-62). RNA analysis of this cell line showed that c.1008G>A abolishes the native donor splice site resulting in three out-of-frame transcripts (Karam R et al. Oncogene 2008 Jul; 27(30):4255-60). Internal RNA splicing analyses of c.1008G>T were consistent with those performed by Karam et al. and showed three out-of-frame transcripts: a 7 base pair insertion, a 25 base pair insertion, and an insertion of intron 7 (Ambry internal data). Additionally, a variant affecting the same nucleotide, c.1008G>T, segregated in a family affected with hereditary diffuse gastric cancer (Guilford P et al. Nature 1998 Mar; 392(6674):402-5). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000639283	SCV000760854	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2021-04-13	criteria provided, single submitter	clinical testing	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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing, which introduces a premature termination codon (PMID: 8127895, 18427545). The resulting mRNA is expected to undergo nonsense-mediated decay. Studies have shown that this variant alters CDH1 gene expression (PMID: 8127895). This variant has been reported in an observed in individual(s) with diffuse gastric cancer (PMID: 27730413). ClinVar contains an entry for this variant (Variation ID: 231647). This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 336 of the CDH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CDH1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.
Myriad Genetics, Inc.	RCV000639283	SCV004043633	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-06-12	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 9537325, Myriad internal data].