Submissions for variant NM_004360.5(CDH1):c.187C>T (p.Arg63Ter)

dbSNP: rs587783047

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328238	SCV000864614	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-29	reviewed by expert panel	curation	The c.187C>T (p.Arg63*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, 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; PMID: 9751616). 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, PM2_Supporting, PS4_Supporting, PM5_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000144590	SCV000261032	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-06-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg63*) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 156496). This premature translational stop signal has been observed in individual(s) with hereditary diffuse gastric cancer (PMID: 9751616, 22020549, 24493355). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency).
Ambry Genetics	RCV000563489	SCV000668982	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-05	criteria provided, single submitter	clinical testing	The p.R63* pathogenic mutation (also known as c.187C>T), located in coding exon 3 of the CDH1 gene, results from a C to T substitution at nucleotide position 187. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation has been reported in families with diffuse gastric cancer and/or lobular breast cancer (Gayther SA et al. Cancer Res. 1998 Sep 15;58(18):4086-9; Suriano G et al. Clin Cancer Res. 2005 Aug 1;11(15):5401-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted 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	RCV000144590	SCV003927001	pathogenic	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PVS1; PS4; PM2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000144590	SCV004045084	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-06-08	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Pathway Genomics	RCV000144590	SCV000189915	pathogenic	Hereditary diffuse gastric adenocarcinoma	2014-07-24	no assertion criteria provided	clinical testing