ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1137+1G>A (rs876660771)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV000230827 SCV001142236 likely pathogenic Hereditary diffuse gastric cancer 2019-08-20 reviewed by expert panel curation The c.1137+1G>A variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong). This variant is present in <1/100,000 alleles in the gnomAD cohort, however it is present in >1/50,000 alleles in the African sub-population (http://gnomad.broadinstitute.org). This variant was found to co-segregate with disease in multiple affected family members, with 3 meioses observed in one family (PP1; PMID: 10477433). This variant has also been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; PMID: 28195815, 10477433). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1_Strong, PS4_Moderate, and PP1.
Ambry Genetics RCV000219632 SCV000278454 pathogenic Hereditary cancer-predisposing syndrome 2020-03-24 criteria provided, single submitter clinical testing The c.1137+1G>A intronic pathogenic mutation results from a G to A substitution 1 nucleotide after coding exon 8 of the CDH1 gene. This alteration was previously described in a family meeting clinical diagnostic criteria for Hereditary Diffuse Gastric Cancer syndrome, in which 4 individuals were diagnosed with diffuse gastric cancer between ages 25-58 (Guilford PJ et al. Hum. Mutat. 1999;14(3):249-55). Another alteration affecting the same splice donor site (CDH1 c.1137G>A) has been observed in multiple HDGC families (Lynch HT et al. Fam Cancer. 2011 Dec;10(4):667-72; More H et al. Hum Mutat. 2007 Feb;28(2):203; <span style="background-color:initial">Kaurah P et al. JAMA 2007 Jun; 297(21):2360-72; Pantelis D et al. Int J Colorectal Dis, 2016 Dec;31:1825-1833) and has been shown to cause abnormal splicing (Karam R et al. Oncogene. 2008 Jul 10;27(30):4255-60). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000230827 SCV000288420 pathogenic Hereditary diffuse gastric cancer 2020-03-18 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 of the CDH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Loss-of-function variants in CDH1 are known to be pathogenic. This particular variant has been reported to segregate in 4 individuals of a family affected with diffuse gastric cancer (PMID: 10477433, 19725995). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000483444 SCV000568305 pathogenic not provided 2018-11-26 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.1137+1G>A or IVS8+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 8 of the CDH1 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant segregated in a kindred, with all four cases of diffuse gastric cancer (Guilford 1999). Based on the current evidence, we consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483444 SCV000889238 likely pathogenic not provided 2017-12-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000230827 SCV000919093 pathogenic Hereditary diffuse gastric cancer 2017-11-20 criteria provided, single submitter clinical testing Variant summary: The CDH1 c.1137+1G>A variant involves the alteration of a conserved intronic nucleotide and 5/5 splice prediction tools predict a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 2/277198 control chromosomes (gnomAD) at a frequency of 0.0000072, which does not exceed the estimated maximal expected allele frequency of a pathogenic CDH1 variant (0.0000283). Multiple publications have cited the variant in affected individuals including one family, which the variant segregates with disease (Guilford_1999). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

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