ClinVar Miner

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

dbSNP: rs1060501244
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328350 SCV000864611 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-11-27 reviewed by expert panel curation The c.2195G>A variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). 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 12 families with HDGC criteria (PS4; PMID: 17545690 15235021 and laboratory internal data). 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): PM2_Supporting, PS3, PS4.
Labcorp Genetics (formerly Invitae), Labcorp RCV000475163 SCV000545459 pathogenic Hereditary diffuse gastric adenocarcinoma 2024-01-21 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 732 of the CDH1 protein (p.Arg732Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with diffuse gastric cancer and lobular breast cancer (PMID: 15235021, 17545690, 18442100, 26072394, 29589180). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 406663). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CDH1 function (PMID: 15235021). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000492116 SCV000580693 pathogenic Hereditary cancer-predisposing syndrome 2022-02-02 criteria provided, single submitter clinical testing The p.R732Q pathogenic mutation (also known as c.2195G>A) is located in coding exon 14 of the CDH1 gene. This alteration results from a G to A substitution at nucleotide position 2195. The arginine at codon 732 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in multiple HDGC patients and families (Brooks-Wilson et al. J Med Genet. 2004 Jul;41 (7):508-17; Kaurah et al. JAMA. 2007 Jun 6;297(21):2360-72; Fujita et al. Am J Surg Pathol. 2012 Nov;36(11):1709-17; Chung DC et al. N Engl J Med 2007 Jul 19; 357(3):283-91; Hakkaart C et al. Fam. Cancer. 2019 01;18(1):83-90). In addition, RT-PCR analysis showed that the p.R732Q alteration resulted in complex splicing and deletion of 32 base pairs at the start of exon 14 by activating a cryptic acceptor site (Kaurah P et al. JAMA. 2007 Jun;297(21):2360-72). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health RCV000492116 SCV000689502 likely pathogenic Hereditary cancer-predisposing syndrome 2022-08-22 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 732 of the CDH1 protein. Splice site prediction tools suggest that this variant may create a new splice acceptor site. An RNA study has reported aberrant splicing utilizing this new splice site, resulting in the deletion of 32 nucleotides from exon 14 and a premature translation stop signal (PMID: 17545690). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals with hereditary diffuse gastric cancer (DGC) and/or lobular breast cancer (LBC) in the literature (PMID: 15235021, 17545690, 17634464, 18442100, 19269290, 22020549, 23073328, 26072394, 26182300, 29589180, 35070997). 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. Based on the available evidence, this variant is classified as Likely Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV001090443 SCV001245994 pathogenic not provided 2024-05-01 criteria provided, single submitter clinical testing CDH1: PP1:Strong, PM2, PS4:Moderate, PP3, PS3:Supporting
Mayo Clinic Laboratories, Mayo Clinic RCV001090443 SCV002522524 likely pathogenic not provided 2021-04-29 criteria provided, single submitter clinical testing PM2, PS3, PS4_moderate
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000475163 SCV003926903 pathogenic Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing PS3; PS4; PM2; PP3 (PMID: 30311375)
Myriad Genetics, Inc. RCV000475163 SCV004043463 likely pathogenic Hereditary diffuse gastric adenocarcinoma 2023-06-15 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15235021, 17545690, 18442100, 22020549, 26072394]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 17545690].
BRCAlab, Lund University RCV000492116 SCV002588963 likely pathogenic Hereditary cancer-predisposing syndrome 2022-08-26 no assertion criteria provided clinical testing

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