Submissions for variant NM_004360.5(CDH1):c.220C>T (p.Arg74Ter)

dbSNP: rs876658932

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328305	SCV001142232	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-29	reviewed by expert panel	curation	The c.220C>T p.(Arg74Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The 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; SCV000288456.3). 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	RCV000227616	SCV000288456	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg74*) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 239891). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000567709	SCV000661607	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-22	criteria provided, single submitter	clinical testing	The p.R74* pathogenic mutation (also known as c.220C>T), located in coding exon 3 of the CDH1 gene, results from a C to T substitution at nucleotide position 220. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation was detected in a patient with gastric cancer diagnosed at age 41 (Llach J et al. Cancers (Basel), 2020 Aug;12). In one study, this variant was observed in 1/7,051 unselected female breast cancer patients and 0/11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). In another study, this variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
Fulgent Genetics, Fulgent Genetics	RCV000763384	SCV000894084	pathogenic	Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian neoplasm; Malignant tumor of prostate	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000567709	SCV001356424	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 3 of the CDH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
GeneDx	RCV003223631	SCV003919397	pathogenic	not provided	2023-04-17	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25123297, 30287823, 30935944, 33471991, 32842532, 34949788)
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000227616	SCV003927005	pathogenic	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PVS1; PS4_Moderate; PM2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000227616	SCV004044326	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.
Baylor Genetics	RCV003475082	SCV004210572	pathogenic	Familial cancer of breast	2021-07-13	criteria provided, single submitter	clinical testing