Submissions for variant NM_004360.5(CDH1):c.1921C>T (p.Gln641Ter)

dbSNP: rs587782750

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328233	SCV001365431	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-25	reviewed by expert panel	curation	The c.1921C>T p.(Gln641Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_supporting). The variant is present in <1/100,000 alleles in the gnomAD cohort (PM2 _supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_supporting; SCV000187340.5). 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.
Ambry Genetics	RCV000132257	SCV000187340	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-22	criteria provided, single submitter	clinical testing	The p.Q641* pathogenic mutation (also known as c.1921C>T), located in coding exon 12 of the CDH1 gene, results from a C to T substitution at nucleotide position 1921. This changes the amino acid from a glutamine to a stop codon within coding exon 12. 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.
Counsyl	RCV000662630	SCV000785306	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2017-07-07	criteria provided, single submitter	clinical testing
Invitae	RCV000662630	SCV001584184	pathogenic	Hereditary diffuse gastric adenocarcinoma	2022-12-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 142826). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is present in population databases (rs587782750, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gln641*) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000662630	SCV002548319	pathogenic	Hereditary diffuse gastric adenocarcinoma	2022-05-03	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1921C>T (p.Gln641X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251462 control chromosomes. c.1921C>T has been reported in the literature in individuals affected with CDH1-related cancers such as Gastric and Lobular Breast Cancer (example, LaDuca_2017, Lowstuter_2017, Xicola_2019, Gao_2021). Three clinical diagnostic laboratories and an expert panel (ClinGen CDH1 Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000662630	SCV004020027	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-03-06	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.