rs587780112
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 c.1360G>A (p.Val454Ile) variant results in a conservative missense change in the Cadherin 3 domain of CDH1. This variant was observed in 4 in 152,164 alleles in the gnomAD v3.1.2 population database. However, this variants has also been observed in more than 10 individuals without GC, DGC, gastric SRC tumours or LBC and whose families do not suggest HDGC (BS2). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 05/22/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA288034/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.1360G>A | p.Val454Ile | missense_variant | 10/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.1177G>A | p.Val393Ile | missense_variant | 9/15 | ||
CDH1 | NM_001317185.2 | c.-189G>A | 5_prime_UTR_variant | 10/16 | |||
CDH1 | NM_001317186.2 | c.-460G>A | 5_prime_UTR_variant | 10/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.1360G>A | p.Val454Ile | missense_variant | 10/16 | 1 | NM_004360.5 | P1 | |
ENST00000563916.1 | n.347+22C>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251472Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135908
GnomAD4 exome AF: 0.0000376 AC: 55AN: 1461844Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24AN XY: 727222
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74332
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:3Benign:1
Uncertain significance, 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_Supporting (PMID: 30311375) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 07, 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 13, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 15, 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 | Apr 03, 2023 | This missense variant replaces valine with isoleucine at codon 454 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 CDH1-related disorders in the literature. This variant has been identified in 6/246246 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 17, 2021 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 04, 2023 | In the published literature, this variant has been reported in individuals and families with breast cancer (PMIDs: 36436516 (2023), 33471991 (2021), 25186627 (2015)), as well as healthy, unaffected individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CDH1)). The frequency of this variant in the general population, 0.00011 (4/35440 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 07, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15235021, 22850631) - |
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 c.1360G>A (p.Val454Ile) variant results in a conservative missense change in the Cadherin 3 domain of CDH1. This variant was observed in 4 in 152,164 alleles in the gnomAD v3.1.2 population database. However, this variants has also been observed in more than 10 individuals without GC, DGC, gastric SRC tumours or LBC and whose families do not suggest HDGC (BS2). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 05/22/2023) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at