Submissions for variant NM_004360.5(CDH1):c.1895_1896del (p.His632fs)

dbSNP: rs1060501224

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328343	SCV001142227	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-25	reviewed by expert panel	curation	The c.1895_1896delAC (p.His632ArgfsTer30) 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 two familes meeting HDGC clinical criteria (PS4_Moderate; PMID 26182300, https://doi.org/10.2147/GICTT.S16330). 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.
Invitae	RCV000468989	SCV000545392	pathogenic	Hereditary diffuse gastric adenocarcinoma	2020-12-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, truncating variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This sequence change deletes 2 nucleotides from exon 12 of the CDH1 mRNA (c.1895_1896delAC), causing a frameshift at codon 632. This creates a premature translational stop signal (p.His632Argfs*30) and is expected to result in an absent or disrupted protein product.
Counsyl	RCV000468989	SCV000677868	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2017-03-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000468989	SCV000698374	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2016-12-09	criteria provided, single submitter	clinical testing	Variant summary: The CDH1 c.1895_1896delAC (p.His632Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent CDH1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 12988 control chromosomes. This variant has been reported in multiple families with strong fx of GC. One of the families showed partial co-segregation of variant with diease, suggesting this variant may be of low penetrance. HDGC is known to be an uncommon hereditary form of GC with variable penetrance, 67% for men and 83% for women (Shenoy_2011). The variant of interest has not, to our knowledge, been reported in affected individuals via reputable databases/clinical diagnostic laboratories; evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Ambry Genetics	RCV002411442	SCV002719498	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-04	criteria provided, single submitter	clinical testing	The c.1895_1896delAC pathogenic mutation, located in coding exon 12 of the CDH1 gene, results from a deletion of two nucleotides at nucleotide positions 1895 to 1896, causing a translational frameshift with a predicted alternate stop codon (p.H632Rfs*30). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Myriad Genetics, Inc.	RCV000468989	SCV004019575	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-03-03	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.