16-68819394-G-C
Variant names:
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_004360.5(CDH1):c.1680G>C(p.Thr560Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00344 in 1,613,740 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0035 ( 26 hom. )
Consequence
CDH1
NM_004360.5 synonymous
NM_004360.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.61
Genes affected
CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
Variant 16-68819394-G-C is Benign according to our data. Variant chr16-68819394-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 136697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-68819394-G-C is described in Lovd as [Likely_benign]. Variant chr16-68819394-G-C is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-3.61 with no splicing effect.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00261 (398/152234) while in subpopulation SAS AF= 0.00519 (25/4816). AF 95% confidence interval is 0.00361. There are 0 homozygotes in gnomad4. There are 195 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 398 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CDH1 | NM_004360.5 | c.1680G>C | p.Thr560Thr | synonymous_variant | Exon 11 of 16 | ENST00000261769.10 | NP_004351.1 | |
| CDH1 | NM_001317184.2 | c.1497G>C | p.Thr499Thr | synonymous_variant | Exon 10 of 15 | NP_001304113.1 | ||
| CDH1 | NM_001317185.2 | c.132G>C | p.Thr44Thr | synonymous_variant | Exon 11 of 16 | NP_001304114.1 | ||
| CDH1 | NM_001317186.2 | c.-254-2607G>C | intron_variant | Intron 10 of 14 | NP_001304115.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.00262 AC: 398AN: 152116Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00337 AC: 848AN: 251482Hom.: 4 AF XY: 0.00386 AC XY: 524AN XY: 135914
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GnomAD4 exome AF: 0.00352 AC: 5151AN: 1461506Hom.: 26 Cov.: 32 AF XY: 0.00366 AC XY: 2662AN XY: 727044
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GnomAD4 genome 0.00261 AC: 398AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.00262 AC XY: 195AN XY: 74422
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:29
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:9
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CDH1 p.Thr560= variant was identified in the literature in 1 of 20 normal chromosomes (frequency: 0.025); however the frequency of this variant in an affected population was not provided (Berx 1997). The variant was also identified in dbSNP (ID: rs35741240) as “With Likely benign, other allele”, in the ClinVar database as benign by GeneDx, Ambry Genetics, EGL Genetic Diagnostics, Invitae, ARUP Laboratories and as likely benign by Illumina Clinical Services; in the Clinvitae database as benign by EmyClass; and in the Cosmic and in Zhejiang Colon Cancer Databases 1X in haemangioblastoma. The variant was not identified in MutDB or the Insight Colon Cancer Gene Variant databases. The variant was further identified in the 1000 Genomes Project in 9 of 5000 chromosomes (frequency: 0.002) and in the NHLBI GO Exome Sequencing Project in 25 of 8600 European American and 3 in 4396 in African American alleles. The variant was identified in control databases in 925 of 277220 chromosomes (4 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 19 of 24022 chromosomes (freq: 0.0008), other in 14 of 6464 chromosomes (freq: 0.002), Latino in 46 of 34420 chromosomes (freq: 0.001), European Non-Finnish in 573 of 126722 chromosomes (freq: 0.004), Ashkenazi Jewish in 8 of 10152 chromosomes (freq: 0.0008), East Asian in 2 of 18868 chromosomes (freq: 0.0001), European Finnish in 52 of 25794 chromosomes (freq: 0.002), and South Asian in 211 of 30778 chromosomes (freq: 0.007). The p.Thr560= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
| Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 29, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2025 | CDH1: BP4, BP7, BS2 - |
not specified Benign:7
| Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 06, 2021 | - - |
| Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
| Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 06, 2017 | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 13, 2013 | 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
| Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 02, 2015 | - - |
Hereditary diffuse gastric adenocarcinoma Benign:7
| Likely benign, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Jan 04, 2018 | CDH1 p.T560T (NM_004360.3:c.1680G>C) has been reported at a frequency of approximately 1 in 100 individuals of European ancestry (exac.broadinstitute.org). This variant frequency is too high to be consistent with the cancer risk syndrome seen with pathogenic CDH1 variants (Hansford 2015). This evidence supports classification of this variant as likely benign. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. - |
| Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 19, 2024 | This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. - |
| Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
| 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 | BA1 (PMID: 30311375) - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 04, 2025 | - - |
| Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Feb 01, 2025 | - - |
Hereditary cancer-predisposing syndrome Benign:4
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 15, 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 07, 2015 | - - |
| Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Apr 26, 2018 | - - |
| Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 10, 2020 | - - |
Breast and/or ovarian cancer Benign:1
| Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 12, 2023 | - - |
Malignant tumor of prostate Benign:1
| Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at