Submissions for variant NM_004360.5(CDH1):c.2398del (p.Arg800fs)

dbSNP: rs587783048

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328239	SCV000864588	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-29	reviewed by expert panel	curation	The c.2398delC (p.Arg800Alafs*16) variant is predicted to result in a premature stop codon that leads to a truncated protein. However, it is located within the nonsense mediated decay resistance region upstream of c.2506G>T (p.Glu836*) (PVS1_Strong). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID 17545690). This variant was also found to co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed (PP1; PMID: 17545690). 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, PP1.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000144591	SCV000545475	pathogenic	Hereditary diffuse gastric adenocarcinoma	2022-08-08	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 156497). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CDH1 protein in which other variant(s) (p.Phe810Leufs*6) have been determined to be pathogenic (PMID: 26182300; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant is also known as a founder mutation that segregated with DGC and LBC in multiple families originating from Newfoundland (PMID: 17545690). This premature translational stop signal has been observed in individual(s) with diffuse gastric cancer (DGC) and lobular breast cancer (LBC) (PMID: 17545690, 23709761, 24366306). It is commonly reported in individuals of Newfoundland ancestry (PMID: 17545690, 23709761, 24366306). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg800Alafs*16) in the CDH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 83 amino acid(s) of the CDH1 protein.
Ambry Genetics	RCV000592579	SCV000700322	pathogenic	Hereditary cancer-predisposing syndrome	2019-06-12	criteria provided, single submitter	clinical testing	The c.2398delC pathogenic mutation, located in coding exon 15 of the CDH1 gene, results from a deletion of one nucleotide at position 2398, causing a translational frameshift with a predicted alternate stop codon (p.R800Afs*16). This mutation was reported in four HDGC families from the southeast coast of Newfoundland who shared a common haplotype, suggesting a founder effect. Based on clinical data obtained from the families, the authors were able to estimate the penetrance of the c.2398delC mutation. The cumulative risk of gastric cancer by age 75 for these four families was estimated to be 40% (95% CI 12%-91%) for males and 63% (95% CI 19%-99%) for females, and a cumulative risk for female breast cancer by age 75 was estimated to be 52% (95% CI 29%-94%) (Kaurah P et al. JAMA. 2007 Jun 6;297(21):2360-72). This alteration was also identified in a patient diagnosed with bilateral LCIS and unilateral ILC in her 30's (Petridis C et al. Br. J. Cancer. 2014 Feb;110(4):1053-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000657198	SCV000778924	pathogenic	not provided	2024-09-03	criteria provided, single submitter	clinical testing	Frameshift variant in the C-terminus predicted to result in protein truncation as the last 82 amino acids are lost and replaced with 15 incorrect amino acids (HGMD); Observed in individuals with hereditary diffuse gastric cancer and invasive lobular breast cancer (PMID: 24366306, 34949788, 23709761, 19269290, 17545690); Co-segregated with hereditary diffuse gastric cancer and lobular breast cancer in multiple families and report as a founder variant in Newfoundland (PMID: 17545690); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24366306, 26759166, 18161866, 19408054, 17545690, 23709761, 18427545, 18007144, 19269290, 22225527, 20373070, 21696387, 18046629, 27752808, 30311375, 29798843, 30745422, 15235021, 22850631, 34949788)
Myriad Genetics, Inc.	RCV000144591	SCV004043603	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-06-15	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Pathway Genomics	RCV000144591	SCV000189917	pathogenic	Hereditary diffuse gastric adenocarcinoma	2014-07-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000657198	SCV001550169	uncertain significance	not provided		no assertion criteria provided	clinical testing