Submissions for variant NM_004360.5(CDH1):c.1999del (p.Leu667fs)

dbSNP: rs786202033

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328252	SCV001437625	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-25	reviewed by expert panel	curation	The c.1999del (p.Leu667fs) 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). This variant has been reported in at least three families meeting HDGC clinical criteria (PS4_Moderate; SCV000329231.6, SCV000950815.1, SCV000215304.5). 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_Moderate, PM5_Supporting.
Ambry Genetics	RCV000164640	SCV000215304	pathogenic	Hereditary cancer-predisposing syndrome	2024-03-05	criteria provided, single submitter	clinical testing	The c.1999delC pathogenic mutation, located in coding exon 13 of the CDH1 gene, results from a deletion of one nucleotide at nucleotide position 1999, causing a translational frameshift with a predicted alternate stop codon (p.L667Sfs*12). This variant has been observed in at least one individual with a personal and/or family history that is consistent with CDH1-related diffuse gastric and lobular breast cancer (Kumar S et al. Clin Gastroenterol Hepatol, 2020 02;18:505-508.e1; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
GeneDx	RCV000376724	SCV000329231	pathogenic	not provided	2024-04-04	criteria provided, single submitter	clinical testing	Frameshift 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: 28152038, 31986421, 31246251, 26556299, 34949788, 31077828, 31296550, 36063148, 32260281)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810597	SCV000950815	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu667Serfs*12) 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 premature translational stop signal has been observed in individual(s) with hereditary diffuse gastric cancer (PMID: 31077828). ClinVar contains an entry for this variant (Variation ID: 185252). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804893	SCV002050835	pathogenic	Malignant tumor of breast	2021-12-09	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1999delC (p.Leu667SerfsX12) 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 was absent in 282864 control chromosomes (gnomAD). c.1999delC has been reported in the literature in individuals affected with Breast Cancer and Hereditary Diffuse Gastric Cancer (examples: Schrader_2016, Zhang_2020, Kumar_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters, including an expert panel (ClinGen CDH1 Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000164640	SCV002052282	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-16	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 13 of the CDH1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least three families meeting hereditary diffuse gastric cancer clinical criteria (ClinVar SCV001437625.1). 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.
Myriad Genetics, Inc.	RCV000810597	SCV004045044	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.
Baylor Genetics	RCV003462145	SCV004215622	pathogenic	Familial cancer of breast	2023-10-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000376724	SCV004220813	pathogenic	not provided	2022-03-11	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the CDH1 mRNA and causes the premature termination of CDH1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals affected with gastric cancer identified during post-surgical pathological examinations (PMID: 31077828 (2020), 31986421 (2020)). In addition, the variant was identified in a woman affected with breast cancer who also carried a truncating ATM c.8793T>A (p.Cys2931*) variant. Based on the available information, this variant is classified as pathogenic.