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

dbSNP: rs1131690818

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328378	SCV004035105	uncertain significance	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-03	reviewed by expert panel	curation	The c.1711+5G>A variant in CDH1 is an intronic variant which switches a G to an A in the +5 position of intron 11. This variant is known in five families, three of which meet HDGC criteria (PS4_moderate; PMID: 15235021, AmbryGenetics, Invitae, Color and CeTaG internal data). This variant is completely absent from population databases such as gnomAD (PM2_supporting). There is evidence of abnormal RNA expression of this variant allele as a functional consequence of incorrect slicing, but further studies are required to confirm this evidence (PS3_supporting; PMID: 15235021). In summary, this variant is classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the ClinGen CDH1 Variant Curation Expert Panel: PS3_supporting, PS4_moderate, PM2_supporting. (CDH1 VCEP specifications version 3.1; 06/26/2023)
Ambry Genetics	RCV000492288	SCV000580708	pathogenic	Hereditary cancer-predisposing syndrome	2017-10-30	criteria provided, single submitter	clinical testing	The c.1711+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 11 in the CDH1 gene. This alteration, referred to as IVS11+5G>A, was reported in an individual diagnosed with diffuse gastric cancer at age 48 who had two family members with confirmed diffuse gastric cancer both at age 44 and five family members with breast cancer, one of which was confirmed as lobular. Additional RT-PCR analyses indicated that this alteration led to exon 11 skipping (Brooks-Wilson AR et al. J Med Genet. 2004 Jul;41(7):508-17). This nucleotide position is highly conserved in available vertebrate species. Based on the available evidence, c.1711+5G>A is classified as a pathogenic mutation.
Invitae	RCV001856947	SCV002274869	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2021-01-20	criteria provided, single submitter	clinical testing	This sequence change falls in intron 11 of the CDH1 gene. It does not directly 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. 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 skipping of exon 11, which introduces a premature termination codon (PMID: 15235021). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant has been observed in individual(s) with hereditary diffuse gastric cancer syndrome (PMID: 15235021, Invitae). ClinVar contains an entry for this variant (Variation ID: 428630). This variant is not present in population databases (ExAC no frequency).
CeGaT Center for Human Genetics Tuebingen	RCV002510906	SCV002822308	uncertain significance	not provided	2022-10-01	criteria provided, single submitter	clinical testing	CDH1: PM2, PP1, PS3:Supporting
Baylor Genetics	RCV003476179	SCV004210561	likely pathogenic	Familial cancer of breast	2022-07-21	criteria provided, single submitter	clinical testing