rs149450874
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS2BP7
This summary comes from the ClinGen Evidence Repository: The c.2451G>A variant is predicted silent and has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). The nucleotide is not conserved (BP7). Therefore, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA186706/MONDO:0007648/007
Frequency
Consequence
NM_004360.5 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.2451G>A | p.Ala817= | synonymous_variant | 16/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.2268G>A | p.Ala756= | synonymous_variant | 15/15 | ||
CDH1 | NM_001317185.2 | c.903G>A | p.Ala301= | synonymous_variant | 16/16 | ||
CDH1 | NM_001317186.2 | c.486G>A | p.Ala162= | synonymous_variant | 15/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.2451G>A | p.Ala817= | synonymous_variant | 16/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 152156Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251462Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135914
GnomAD4 exome AF: 0.000144 AC: 211AN: 1461820Hom.: 0 Cov.: 32 AF XY: 0.000144 AC XY: 105AN XY: 727228
GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152274Hom.: 1 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74456
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Benign:5
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. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | May 02, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de InvestigaĆ§Ć£o e InovaĆ§Ć£o em SaĆŗde, University of Porto | Aug 01, 2022 | BS2; BP7 (PMID: 30311375) - |
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 06, 2023 | This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 28, 2019 | Variant summary: CDH1 c.2451G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.9e-05 in 277230 control chromosomes. The observed variant frequency is approximately 2.42 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2451G>A in individuals affected with Hereditary Diffuse Gastric Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant five times as likely benign/benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 05, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 2015 | 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. - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 02, 2015 | This alteration is classified as likely 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. - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 26, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 16, 2015 | - - |
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 06, 2019 | - - |
CDH1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 21, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2022 | CDH1: BP4, BP7 - |
CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Aug 17, 2023 | The c.2451G>A variant is predicted silent and has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). The nucleotide is not conserved (BP7). Therefore, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP7. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at