Submissions for variant NM_004360.5(CDH1):c.12G>A (p.Trp4Ter)

dbSNP: rs1555509636

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328454	SCV001142267	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-04	reviewed by expert panel	curation	The c.12G>A (p.Trp4Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, 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 (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting.
Counsyl	RCV000662736	SCV000785509	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2017-08-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002386135	SCV002692474	pathogenic	Hereditary cancer-predisposing syndrome	2024-07-18	criteria provided, single submitter	clinical testing	The p.W4* variant (also known as c.12G>A), located in coding exon 1 of the CDH1 gene, results from a G to A substitution at nucleotide position 12. This changes the amino acid from a tryptophan to a stop codon within coding exon 1. This alteration was identified in an individual at risk for hereditary cancer referred for multigene panel testing (Schroeder C et al. Breast Cancer Res. Treat. 2015 Jul;152(1):129-136). The predicted stop codon for this alteration occurs within the first 150 nucleotides of the CDH1 gene. Therefore, this alteration may escape nonsense-mediated mRNA decay and/or be rescued by reinitiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). However, the impacted region is critical for protein function (van Roy F et al. Cell. Mol. Life Sci. 2008 Nov;65(23):3756-88; Shapiro L et al. Cold Spring Harb Perspect Biol 2009 Sep;1(3):a003053; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV002386135	SCV004360420	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-09	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 1 of the CDH1 gene, creating a premature translation stop signal. This variant is expected to disrupt the signal sequence of the protein and result in an absent or non-functional protein product. To our knowledge, this variant has been reported in an individual with a high-risk family profile indicative for hereditary breast and ovarian cancer (PMID: 26022348). 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.	RCV000662736	SCV005404515	pathogenic	Hereditary diffuse gastric adenocarcinoma	2024-08-27	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000662736	SCV005838307	pathogenic	Hereditary diffuse gastric adenocarcinoma	2024-07-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp4*) 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 CDH1-related conditions (PMID: 26022348). ClinVar contains an entry for this variant (Variation ID: 548782). For these reasons, this variant has been classified as Pathogenic.