rs35572355
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS2BS1
This summary comes from the ClinGen Evidence Repository: The c.2494G>A (p.Val832Met) variant has an allele frequency of 0.00175 (0.175%, 33/18,868 alleles) in the East Asian subpopulation of the gnomAD cohort (BS1). This 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, 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): BS1, BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA157969/MONDO:0007648/007
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.2494G>A | p.Val832Met | missense_variant | 16/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.2311G>A | p.Val771Met | missense_variant | 15/15 | ||
CDH1 | NM_001317185.2 | c.946G>A | p.Val316Met | missense_variant | 16/16 | ||
CDH1 | NM_001317186.2 | c.529G>A | p.Val177Met | missense_variant | 15/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.2494G>A | p.Val832Met | missense_variant | 16/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000167 AC: 42AN: 251488Hom.: 0 AF XY: 0.000228 AC XY: 31AN XY: 135918
GnomAD4 exome AF: 0.000153 AC: 223AN: 1461892Hom.: 1 Cov.: 32 AF XY: 0.000165 AC XY: 120AN XY: 727248
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152262Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74432
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Pathogenic:1Uncertain:1Benign:3
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 07, 2018 | - - |
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 | BS1; BS2 (PMID: 30311375) - |
Likely pathogenic, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 21, 2017 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 11, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 16, 2019 | 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. - |
not specified Benign:2Other:1
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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 18, 2020 | Variant summary: CDH1 c.2494G>A (p.Val832Met) results in a conservative amino acid change located in the Cadherin, cytoplasmic domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 253888 control chromosomes, predominantly at a frequency of 0.0017 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 60 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 East Asian origin. c.2494G>A, has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer (Yabuta_2002, Kim_2017), Breast Cancer (Schrader_2011, Rummel_2017, Siraj_2017), Lynch Syndrome (Yurgelun_2015), and Pancreatic Cancer (Shindo_2017, Ohmoto_2015). A publication, Yabuta_2002, reports the variant to segregate with disease in a HDGC family. Furthermore, a tumor obtained from a patient with this variant harbored a CDH1 promoter hypermethylation as a second hit leading to somatic loss of heterozygosity (Oliveira_2009). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. At-least two co-occurrences with other pathogenic variant(s) have been observed (Siraj_2017-FANCI c.2737C>T, p.Q913X; our laboratory-BRCA2 c.5576_5579delTTAA, p.Ile1859fs), providing supporting evidence for a benign role. Multiple functional studies showed no significant effect of this variant on cell mobility and cell invasion (Suriano_2003), interaction with alpha/beta catenin (Bajpai_2008), cell surface expression, EGFR signaling, and beta catenin binding (Mateaus_2009, Yabuta_2002, Curtis_2007). In addition, Clinical Genome Resource (ClinGen) variant curation expert panel (VCEP) recently classified this variant as benign (Lee_2018). Ten clinical diagnostic laboratories and one expert panel (ClinGen CDH1 Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments (likely benign, n=3, benign, n=1). Several submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign. - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 13, 2019 | This variant is associated with the following publications: (PMID: 12216071, 26759166, 28004449, 26692440, 20373070, 29050249, 16924464, 19268661, 22850631, 24055113, 24728327, 17668349, 12944922, 17261850, 16600987, 25388006, 25856671, 25637381, 17545690, 20233471, 26150395, 20921021, 16787116, 28503720, 14500541, 19269290, 26049741, 25980754, 22470475, 19017792, 29231860, 28975465, 28767289, 29522266, 29929997, 29752822, 16112667, 21989054, 19247957, 31159747, 31892987, 32426482) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 27, 2019 | - - |
Neoplasm of stomach Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
DIFFUSE GASTRIC AND LOBULAR BREAST CANCER SYNDROME Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 10, 2002 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Cancer Genomics Group, Japanese Foundation For Cancer Research | May 01, 2019 | - - |
CDH1-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 21, 2020 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
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.2494G>A (p.Val832Met) variant has an allele frequency of 0.00175 (0.175%, 33/18,868 alleles) in the East Asian subpopulation of the gnomAD cohort (BS1). This 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, 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): BS1, BS2. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at