Submissions for variant NM_004360.5(CDH1):c.48+1G>A

dbSNP: rs1440280370

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328391	SCV000864610	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-29	reviewed by expert panel	curation	The c.48+1G>A 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). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; PMID: 20719348, 24366306). The variant was also found to co-segregate with disease in multiple affected family members, with 5 or 6 meioses observed (PP1_Moderate; SCV000617359.1). 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_Strong, PM2_Supporting, PS4_Moderate and PP1_Moderate, PM5_Supporting.
GeneDx	RCV000523956	SCV000617359	pathogenic	not provided	2017-07-20	criteria provided, single submitter	clinical testing	This variant is denoted CDH1 c.48+1G>A or IVS1+1G>A and consists of a G>A nucleotide substitutionat the +1 position of intron 1 of the CDH1 gene. This variant destroys a canonical splice donor site and is predicted tocause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNAdecay or to an abnormal protein product. CDH1 c.48+1G>A has been reported in at least two families; one presentingwith multiple cases of diffuse gastric cancer while the other is reported to only have lobular breast cancer (Pandalai2011, Petridis 2014). Based on the current evidence, we consider this variant to be pathogenic
Mendelics	RCV000709393	SCV000839072	pathogenic	Hereditary diffuse gastric adenocarcinoma	2018-07-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002341220	SCV002636427	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-01	criteria provided, single submitter	clinical testing	The c.48+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 1 of the CDH1 gene. This alteration has been reported in a family affected with gastric cancers, colon cancer, and signet cell carcinoma of the cecum. Three unaffected members of this family were found to carry the c.48+1G>A pathogenic mutation and elected prophylactic gastrectomies. Post-surgical evaluations of all three gastrectomy specimens showed multiple foci of intramucosal adenocarcinoma and/or of signet ring cell carcinoma in situ (Pandalai PK et al. Surgery. 2011 Mar;149(3):347-55; Fujita H et al. Am J Surg Pathol. 2012 Nov;36(11):1709-17). This mutation has also been reported in one individual with a family history of breast cancer and a personal history of bilateral lobular breast cancer in situ (LCIS) and bilateral invasive lobular breast cancer (ILC) diagnosed at age 51 (Petridis C et al. Br J Cancer. 2014 Feb 18;110(4):1053-7). In addition to the clinical data presented in the literature, 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.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000709393	SCV003926759	pathogenic	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PVS1_Strong; PS4_Moderate; PM2; PP1_Moderate (PMID: 30311375)
Myriad Genetics, Inc.	RCV000709393	SCV004043477	pathogenic	Hereditary diffuse gastric adenocarcinoma	2024-08-27	criteria provided, single submitter	clinical testing	This variant is considered 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. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 20719348, 38873722, 30745422].