ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1895_1896del (p.His632fs) (rs1060501224)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV000468989 SCV001142227 pathogenic Hereditary diffuse gastric cancer 2019-08-20 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). The variant is absent in the gnomAD cohort (PM2; 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: PVS1, PM2, PS4_Moderate.
Invitae RCV000468989 SCV000545392 pathogenic Hereditary diffuse gastric cancer 2016-10-16 criteria provided, single submitter clinical testing 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. While this particular variant has not been reported in the literature, truncating variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000468989 SCV000677868 likely pathogenic Hereditary diffuse gastric cancer 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 cancer 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.

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