rs587780113
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2_SupportingPS3_ModeratePS4PVS1_StrongPP1_StrongPM5_Supporting
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CV127915/MONDO:0007648/007
Frequency
Consequence
NM_004360.5 splice_donor, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CDH1 | NM_004360.5 | c.1565+1G>A | splice_donor_variant, intron_variant | Intron 10 of 15 | ENST00000261769.10 | NP_004351.1 | ||
| CDH1 | NM_001317184.2 | c.1382+1G>A | splice_donor_variant, intron_variant | Intron 9 of 14 | NP_001304113.1 | |||
| CDH1 | NM_001317185.2 | c.17+1G>A | splice_donor_variant, intron_variant | Intron 10 of 15 | NP_001304114.1 | |||
| CDH1 | NM_001317186.2 | c.-255+1G>A | splice_donor_variant, intron_variant | Intron 10 of 14 | NP_001304115.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Pathogenic:5Other:3
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. -
PVS1_Strong; PS4_Moderate; PM2 (PMID: 30311375) -
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. -
_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP -
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 (internal data). For these reasons, this variant has been classified as Pathogenic. -
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. -
- -
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. -
Familial cancer of breast Pathogenic:3
- -
- -
PVS1_STR, PS4_STR, PS3, PM2_SUP, PP1 -
not provided Pathogenic:2Other:1
- -
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) -
The CHD1 c.1565+1G>A variant (rs587780113, ClinVar variation ID: 127915) is reported in the literature in numerous individuals affected with breast, gastric, or colorectal cancer (selected references: Adib 2022, Garcia-Pelaez 2023, Hansford 2015, Lo 2019, Schrader 2008). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. RNAseq analysis of mRNA demonstrate altered splicing (Casadei 2019). This variant disrupts the canonical splice donor site of intron 10, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: Adib E et al. CDH1 germline variants are enriched in patients with colorectal cancer, gastric cancer, and breast cancer. Br J Cancer. 2022 Mar;126(5):797-803. PMID: 34949788. Casadei S et al. Characterization of splice-altering mutations in inherited predisposition to cancer. Proc Natl Acad Sci U S A. 2019 Dec 26;116(52):26798-26807. PMID: 31843900. Garcia-Pelaez J et al. Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes. Lancet Oncol. 2023 Jan;24(1):91-106. PMID: 36436516. Hansford S et al. Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond. JAMA Oncol. 2015 Apr;1(1):23-32. PMID: 26182300. Lo W et al. Associations of CDH1 germline variant location and cancer phenotype in families with hereditary diffuse gastric cancer (HDGC). J Med Genet. 2019 Jun;56(6):370-379. PMID: 30745422. Schrader KA et al. Hereditary diffuse gastric cancer: association with lobular breast cancer. Fam Cancer. 2008;7(1):73-82. PMID: 18046629. -
Hereditary cancer-predisposing syndrome Pathogenic:2
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. -
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. -
Familial cancer of breast;C1708349:Hereditary diffuse gastric adenocarcinoma Pathogenic:1
- -
CDH1-related diffuse gastric and lobular breast cancer syndrome Pathogenic:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at