Submissions for variant NM_004360.5(CDH1):c.1711+1G>C

dbSNP: rs886041161

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328318	SCV001142271	likely pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-24	reviewed by expert panel	curation	The c.1711+1G>C 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). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000329230.6). 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_Supporting, PM5_Supporting.
GeneDx	RCV000322113	SCV000329230	pathogenic	not provided	2015-08-25	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted CDH1 c.1711+1 G>C or IVS11+1 G>C and consists of a G>C nucleotide substitution at the +1 position of intron 11 of the CDH1 gene. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in a lobular breast tumor (Sarrio 2003). We therefore consider this variant to be pathogenic.
MGZ Medical Genetics Center	RCV000991099	SCV002579171	pathogenic	Hereditary diffuse gastric adenocarcinoma	2022-07-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002401972	SCV002712927	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-01-16	criteria provided, single submitter	clinical testing	The c.1711+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 11 of the CDH1 gene. This variant has been reported in an individual with lobular breast cancer and in a cleft lip/palate (CLP) / hereditary diffuse gastric cancer (HDGC) family (Sarrió D et al. Int J Cancer, 2003 Aug;106:208-15, Obermair F et al. Fam Cancer, 2019 04;18:253-260). 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. 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 majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000991099	SCV003787067	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 11 of the CDH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with hereditary diffuse gastric cancer (PMID: 30306390). ClinVar contains an entry for this variant (Variation ID: 279747). Studies have shown that disruption of this splice site results in skipping of exon 11 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.