rs1801023
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP2BA1
This summary comes from the ClinGen Evidence Repository: The c.345G>A variant has an allele frequency of 0.007677 (0.77%, 235/30,612 alleles, 4 homozygotes) in the South Asian subpopulation of the gnomAD cohort (BA1, BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA293902/MONDO:0007648/007
Frequency
Consequence
NM_004360.5 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.345G>A | p.Thr115= | synonymous_variant | 3/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.345G>A | p.Thr115= | synonymous_variant | 3/15 | ||
CDH1 | NM_001317185.2 | c.-1271G>A | 5_prime_UTR_variant | 3/16 | |||
CDH1 | NM_001317186.2 | c.-1475G>A | 5_prime_UTR_variant | 3/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.345G>A | p.Thr115= | synonymous_variant | 3/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00262 AC: 398AN: 152168Hom.: 3 Cov.: 32
GnomAD3 exomes AF: 0.00372 AC: 933AN: 251082Hom.: 5 AF XY: 0.00417 AC XY: 566AN XY: 135694
GnomAD4 exome AF: 0.00373 AC: 5456AN: 1461852Hom.: 25 Cov.: 32 AF XY: 0.00383 AC XY: 2786AN XY: 727222
GnomAD4 genome ? AF: 0.00261 AC: 397AN: 152286Hom.: 3 Cov.: 32 AF XY: 0.00282 AC XY: 210AN XY: 74466
ClinVar
Submissions by phenotype
not specified Benign:10
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 19, 2017 | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 08, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Likely benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 09, 2021 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Hereditary diffuse gastric adenocarcinoma Benign:3
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, 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 | BA1; BP2_Strong (PMID: 30311375) - |
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 13, 2015 | - - |
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Jun 18, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 23, 2014 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 01, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | CDH1: BP4, BP7, BS2 - |
CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:1
Benign, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Aug 10, 2023 | The c.345G>A variant has an allele frequency of 0.007677 (0.77%, 235/30,612 alleles, 4 homozygotes) in the South Asian subpopulation of the gnomAD cohort (BA1, BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. - |
Malignant tumor of prostate Benign:1
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CDH1 p.Thr115Thr variant was identified in 6 of 380 proband chromosomes (frequency: 0.016) from individuals or families with gastric cancer, other cancer types and normal individuals (Garziera 2013) and was present in 1 of 40 control chromosomes (frequency: 0.025) from healthy individuals (Berx 1997). The variant was also identified in dbSNP (ID: rs1801023) as “With other allele”, ClinVar (6x, as benign by Invitae, GeneDx, Ambry Genetics, Prevention Genetics, Color Genomics, as likely benign by Illumina), Clinvitae (3x as benign ), Zhejiang Colon Cancer Database. The variant was not identified in Cosmic, MutDB, databases. The variant was identified in control databases in 991 of 276784 (5 homozygous) chromosomes at a frequency of 0.0036 in the following populations: African in 12 of 24020 chromosomes (freq. 0.0005), other in 26 of 6460 chromosomes (freq. 0.004), Latino in 72 of 34410 chromosomes (freq. 0.002), European in 518 of 126334 chromosomes (freq. 0.0041), Ashkenazi Jewish in 109 of 10130 chromosomes (freq. 0.01), East Asian in 3 of 18868 chromosomes (freq. 0.00016), Finnish in 15 of 25784 chromosomes (freq. 0.0006), and South Asian in 236 of 30778 chromosomes (freq. 0.0076),.increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Thr115Thr variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at