ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1565+1G>A

dbSNP: rs587780113
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328172 SCV001943329 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-30 reviewed by expert panel curation The c.1565+1G>A variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least six families meeting HDGC clinical criteria (PS4; PMID: 26182300, SCV000149752.12 and internal laboratory contributor). This variant was also found to co-segregate with disease in multiple affected family members, with nine meioses observed across at least five families (PP1_Strong; SCV000149752.12 and internal laboratory contributor). The c.1565+1G>A allele was demonstrated to alter splicing through RNASeq analysis of mRNA from an affected carrier (PS3_Moderate; PMID: 31843900). 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, PS4, PP1_Strong, PS3_Moderate, PM2_Supporting.
GeneDx RCV000212372 SCV000149752 pathogenic not provided 2023-07-28 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Observed in families with a history of cleft lip and palate in published literature (Green et al., 2022); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20373070, 25525159, 24506336, 27064202, 18046629, 27153395, 25986922, 26182300, 30745422, 26681312, 31986421, 30641862, 36436516, 34949788, 36246616)
Labcorp Genetics (formerly Invitae), Labcorp RCV000123238 SCV000166544 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-12-05 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 10 of the CDH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with breast cancer and diffuse gastric cancer (PMID: 18046629, 26182300, 27064202, 27153395). ClinVar contains an entry for this variant (Variation ID: 127915). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000115843 SCV000184644 pathogenic Hereditary cancer-predisposing syndrome 2023-01-06 criteria provided, single submitter clinical testing The c.1565+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 10 of the CDH1 gene. This mutation has been reported as pathogenic in a lobular breast cancer patient, whose family history was significant primarily for multiple breast cancers and also one early-onset gastric cancer (Schrader KA et al. Fam Cancer. 2008;7:73-82). In addition, a second splicing mutation at this position, c.1565+1G>T, has been detected in a diffuse gastric cancer family (Humar B et al. Hum Mutat. 2002;19(5):518-25). Of note, this mutation is also called IVS10+1G>A in published literature. 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 clinical data presented in the literature, 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.
Color Diagnostics, LLC DBA Color Health RCV000115843 SCV000689462 pathogenic Hereditary cancer-predisposing syndrome 2022-01-20 criteria provided, single submitter clinical testing This variant causes a G>A nucleotide substitution at the canonical +1 position of intron 10 splice donor of the CDH1 gene. RNA studies have shown that this variant results in the use of a cryptic splice site, resulting in a 6 bp message insertion and premature stop at codon 523 (PMID: 31843900). This variant has been reported in individuals affected with breast and diffuse gastric cancer (PMID: 18046629, 24506336, 26182300, 26681312, 27064202, 27153395, 33322525; Lowstuter 2017, DOI: 10.1200/PO.16.00021). Different DNA subsitution variants at the +1 G nucleotide position have also been reported in individuals and families affected with diffuse gastric cancer (PMID: 11968084, 18788075, 26182300). 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 Pathogenic.
Counsyl RCV000123238 SCV000785623 pathogenic Hereditary diffuse gastric adenocarcinoma 2017-10-16 criteria provided, single submitter clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV001310107 SCV001499640 pathogenic Familial cancer of breast 2020-04-02 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001310107 SCV002762809 pathogenic Familial cancer of breast 2022-12-09 criteria provided, single submitter research PVS1_STR, PS4_STR, PS3, PM2_SUP, PP1
Institute of Human Genetics, University of Leipzig Medical Center RCV000123238 SCV003921061 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-02-22 criteria provided, single submitter clinical testing _x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000123238 SCV003926813 likely pathogenic Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing PVS1_Strong; PS4_Moderate; PM2 (PMID: 30311375)
Myriad Genetics, Inc. RCV000123238 SCV004020059 likely pathogenic Hereditary diffuse gastric adenocarcinoma 2023-03-07 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.
Baylor Genetics RCV001310107 SCV004215717 pathogenic Familial cancer of breast 2023-06-07 criteria provided, single submitter clinical testing
King Laboratory, University of Washington RCV001171458 SCV001251369 pathogenic Familial cancer of breast; Hereditary diffuse gastric adenocarcinoma 2019-09-01 no assertion criteria provided research
GenomeConnect - No Stomach For Cancer RCV000123238 SCV001338684 not provided Hereditary diffuse gastric adenocarcinoma no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 09-30-2011 by Lab or GTR ID 61756. GenomeConnect- No Stomach for Cancer assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.
MutSpliceDB: a database of splice sites variants effects on splicing, NIH RCV000212372 SCV001976633 not provided not provided no assertion provided research
GenomeConnect, ClinGen RCV000123238 SCV002074898 not provided Hereditary diffuse gastric adenocarcinoma no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 07-15-2020 by Lab or GTR ID 61756. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
GenomeConnect - Invitae Patient Insights Network RCV000123238 SCV004228933 not provided Hereditary diffuse gastric adenocarcinoma no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 12-10-2015 by Lab Myriad. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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