rs33963999
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP2BA1
This summary comes from the ClinGen Evidence Repository: The NM_004360.5(CDH1):c.531+10G>C variant has an allele frequency of 0.05787 (5.787%, 1453/25106 alleles, 39 homozygotes) in the African subpopulation of the gnomAD v2.1.1 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/CA169542/MONDO:0007648/007
Frequency
Consequence
NM_004360.5 intron
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.531+10G>C | intron_variant | ENST00000261769.10 | |||
CDH1 | NM_001317184.2 | c.531+10G>C | intron_variant | ||||
CDH1 | NM_001317185.2 | c.-1085+10G>C | intron_variant | ||||
CDH1 | NM_001317186.2 | c.-1289+10G>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.531+10G>C | intron_variant | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0380 AC: 5790AN: 152172Hom.: 174 Cov.: 32
GnomAD3 exomes AF: 0.0385 AC: 9672AN: 251068Hom.: 254 AF XY: 0.0391 AC XY: 5312AN XY: 135756
GnomAD4 exome AF: 0.0538 AC: 78655AN: 1461656Hom.: 2440 Cov.: 33 AF XY: 0.0527 AC XY: 38312AN XY: 727122
GnomAD4 genome ? AF: 0.0380 AC: 5792AN: 152290Hom.: 175 Cov.: 32 AF XY: 0.0381 AC XY: 2840AN XY: 74464
ClinVar
Submissions by phenotype
not specified Benign:6
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
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, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 22, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Hereditary diffuse gastric adenocarcinoma Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
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. - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 10, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 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. - |
Malignant tumor of breast Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | CDH1, EXON4, c.531+10G>C, p.?, Heterozygous, BenignrnThe CDH1 c.531+10G>C variant was identified in 7 of 194 proband chromosomes (frequency: 0.036) from individuals or families with gastric cancer and colorectal cancer, but the variant was classified as a benign polymorphism in these studies (Berx 1997, Oliveira 2002, Verma 2001). The variant was also identified in dbSNP (rs: rs33963999) as other, ClinVar 5x (classified as benign by multiple submitters), and the Zhejiang Colon Cancer Database (3x). The variant was not identified in Cosmic, MutDB, or Insight Colon Cancer Gene Variant Database. The variant was identified in control databases in 10752 of 276938 chromosomes at a frequency of 0.0388 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: European (Finnish) in 1496 (42 homozygous) of 25776 chromosomes (freq: 0.058), European (Non-Finnish) in 6956 (196 homozygous) of 126510 chromosomes (freq: 0.055), Ashkenazi Jewish* in 404 (11 homozygous) of 10146 chromosomes (freq: 0.04), Other in 245 (8 homozygous) of 6458 chromosomes (freq: 0.038), Latino in 750 (13 homozygous) of 34410 chromosomes (freq: 0.022), South Asian in 665 (12 homozygous) of 30780 chromosomes (freq: 0.022). The variant occurs outside of the splicing consensus sequence and 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 this variant meets our laboratory's criteria to be classified as benign. - |
Malignant tumor of prostate Benign:1
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
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 NM_004360.5(CDH1):c.531+10G>C variant has an allele frequency of 0.05787 (5.787%, 1453/25106 alleles, 39 homozygotes) in the African subpopulation of the gnomAD v2.1.1 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at