rs201637081
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
This summary comes from the ClinGen Evidence Repository: The NM_004360.5(CDH1):c.2020A>T (p.Asn674Tyr) variant 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). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 06/26/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA294385/MONDO:0100488/007
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.2020A>T | p.Asn674Tyr | missense_variant | 13/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.1837A>T | p.Asn613Tyr | missense_variant | 12/15 | ||
CDH1 | NM_001317185.2 | c.472A>T | p.Asn158Tyr | missense_variant | 13/16 | ||
CDH1 | NM_001317186.2 | c.55A>T | p.Asn19Tyr | missense_variant | 12/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.2020A>T | p.Asn674Tyr | missense_variant | 13/16 | 1 | NM_004360.5 | P1 | |
ENST00000563916.1 | n.45T>A | non_coding_transcript_exon_variant | 1/3 | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152150Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000835 AC: 21AN: 251484Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135916
GnomAD4 exome AF: 0.0000390 AC: 57AN: 1461858Hom.: 0 Cov.: 32 AF XY: 0.0000426 AC XY: 31AN XY: 727238
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152150Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74324
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 06, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 08, 2017 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 08, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 25, 2018 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 05, 2023 | This missense variant replaces asparagine with tyrosine at codon 674 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 25/282876 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 05, 2020 | Variant summary: CDH1 c.2020A>T (p.Asn674Tyr) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251484 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4-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 a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.2020A>T in individuals affected with Hereditary Diffuse Gastric Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 20, 2021 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: no PMID, 22850631, 15235021) - |
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 03, 2023 | The NM_004360.5(CDH1):c.2020A>T (p.Asn674Tyr) variant 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). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 06/26/2023) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at