ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.832+1G>A

dbSNP: rs878854697
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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 RCV003328403 SCV001244349 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2024-03-25 reviewed by expert panel curation The CDH1 c.832+1G>A variant is a canonical splice variant in intron 6 predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). The variant is absent from the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been observed in three families meeting IGCLC criteria for HDGC (PS4_Moderate, internal clinical lab data). This variant has also been reported in the literature in families with LBC who do not meet criteria for HDGC (PMID: 36436516, 32489267, 34643667). RNA analysis demonstrated two out-of-frame transcripts, r.754_832del79 p.(V252Efs*4) and r.688_832del145 p.(L230Efs*4) (PS3; internal clinical lab 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): PVS1_Strong, PS3, PS4_Moderate, PM2_Supporting, PM5_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV000552098 SCV000637855 pathogenic Hereditary diffuse gastric adenocarcinoma 2021-03-26 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). Disruption of this splice site has been observed in individual(s) with diffuse gastric cancer (PMID: 23124477, 23709761, 26182300). ClinVar contains an entry for this variant (Variation ID: 463795). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 6 of the CDH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000755032 SCV000882852 pathogenic Hereditary cancer-predisposing syndrome 2018-10-24 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001811046 SCV001158309 pathogenic not provided 2019-08-10 criteria provided, single submitter clinical testing The CDH1 c.832+1G>A variant, to our knowledge, is not reported in the medical literature but is reported as likely pathogenic/pathogenic in ClinVar (Variation ID: 463795). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. A different variant at this codon, c.832+1G>T, is reported in the literature in an individual with hereditary diffuse gastric cancer (Benusiglio 2013). This is an intronic variant in a highly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by abolishing the nearby canonical donor splice site. Based on available information, this variant is considered to be pathogenic. REFERENCES Benusiglio PR et al. Cleft lip, cleft palate, hereditary diffuse gastric cancer and germline mutations in CDH1. Int J Cancer. 2013 May 15;132(10):2470.
Color Diagnostics, LLC DBA Color Health RCV000755032 SCV001356969 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-15 criteria provided, single submitter clinical testing This variant causes a G>A nucleotide substitution at the +1 position of intron 6 of the CDH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
Ambry Genetics RCV000755032 SCV002681995 pathogenic Hereditary cancer-predisposing syndrome 2023-11-09 criteria provided, single submitter clinical testing The c.832+1G>A pathogenic intronic mutation results from a G to A substitution one nucleotide after coding exon 6 of the CDH1 gene. This nucleotide position is highly conserved in available vertebrate species. Another mutation at this position (c.832+1G>T) was reported in a 17-year-old patient with diffuse gastric cancer and history of cleft lip with cleft palate, and in a proband with a personal and family history of diffuse gastric cancer (Benusiglio PR et al. Int. J. Cancer 2013 May;132:2470; Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the available clinical data, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Myriad Genetics, Inc. RCV000552098 SCV004044979 likely pathogenic Hereditary diffuse gastric adenocarcinoma 2023-06-12 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001357495 SCV001552981 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The CDH1 c.832+1G>A variant was identified in 1 of 86 proband chromosomes (frequency: 0.01) from individuals or families with diffuse gastric cancer (Brooks-Wilson 2004). The variant was also identified in ClinVar (classified as likely pathogenic by Invitae) and Cosmic (2x in breast tissue). The variant was not identified in dbSNP, the Zhejiang University Database, or the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.832+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. It is predicted that the aberrant splicing would result in an in-frame deletion of exon 5 from the transcript, which is expected to be deleterious to the protein function (Brooks-Wilson 2004). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
BRCAlab, Lund University RCV000755032 SCV002588960 pathogenic Hereditary cancer-predisposing syndrome 2022-08-26 no assertion criteria provided clinical testing

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