ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2195G>A (p.Arg732Gln) (rs1060501244)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492116 SCV000580693 pathogenic Hereditary cancer-predisposing syndrome 2017-09-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
ClinGen CDH1 Variant Curation Expert Panel RCV000475163 SCV000864611 likely pathogenic Hereditary diffuse gastric cancer 2018-11-21 reviewed by expert panel curation The c.2195G>A (p.Arg732Gln) variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). This variant is predicted to affect splicing by at least 3 in silico splicing predictors in agreement (PP3). Additionally, there is an RNA assay demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID: 17545690 15235021). This variant has also been reported in at least 2 families meeting HDGC clinical criteria (PS4_Moderate; PMID: 17545690 15235021). 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: PM2, PP3, PS3, PS4_Moderate.
Color RCV000492116 SCV000689502 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-30 criteria provided, single submitter clinical testing
Invitae RCV000475163 SCV000545459 pathogenic Hereditary diffuse gastric cancer 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 732 of the CDH1 protein (p.Arg732Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with diffuse gastric cancer and lobular breast cancer (PMID: 15235021, 17545690, 18442100, 26072394). It was reported to segregate with disease in one family, although there were unaffected carriers in the family (PMID: 17545690, 18442100). ClinVar contains an entry for this variant (Variation ID: 406663). Experimental studies have shown that this missense change results in decreased cell aggregation and increased cell invasion (PMID: 15235021). It also likely results in the activation of a cryptic acceptor splice site, leading to disrupted RNA splicing (PMID: 17545690). For these reasons, this variant has been classified as Pathogenic.

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