rs587780113
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_004360.5(CDH1):c.1565+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: not found (cov: 32)
Consequence
CDH1
NM_004360.5 splice_donor
NM_004360.5 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.33
Genes affected
CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 22 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 16-68815760-G-A is Pathogenic according to our data. Variant chr16-68815760-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 127915.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr16-68815760-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.1565+1G>A | splice_donor_variant | ENST00000261769.10 | |||
CDH1 | NM_001317184.2 | c.1382+1G>A | splice_donor_variant | ||||
CDH1 | NM_001317185.2 | c.17+1G>A | splice_donor_variant | ||||
CDH1 | NM_001317186.2 | c.-255+1G>A | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.1565+1G>A | splice_donor_variant | 1 | NM_004360.5 | P1 | |||
ENST00000563916.1 | n.264-101C>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13Other:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Pathogenic:5Other:3
Likely pathogenic, criteria provided, single submitter | clinical testing | European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto | Aug 01, 2022 | PVS1_Strong; PS4_Moderate; PM2 (PMID: 30311375) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 05, 2023 | 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. - |
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 22, 2023 | _x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 07, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 16, 2017 | - - |
not provided, no classification provided | phenotyping only | GenomeConnect - No Stomach For Cancer | - | 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. - |
Familial cancer of breast Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 07, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
Pathogenic, criteria provided, single submitter | research | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 09, 2022 | PVS1_STR, PS4_STR, PS3, PM2_SUP, PP1 - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 20, 2022 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 06, 2023 | 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. - |
not provided Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 28, 2023 | 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) - |
not provided, no classification provided | research | MutSpliceDB: a database of splice sites variants effects on splicing, NIH | - | - - |
Familial cancer of breast;C1708349:Hereditary diffuse gastric adenocarcinoma Pathogenic:1
Pathogenic, no assertion criteria provided | research | King Laboratory, University of Washington | Sep 01, 2019 | - - |
CDH1-related diffuse gastric and lobular breast cancer syndrome Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Aug 30, 2023 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 5
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at