rs33935154
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1
This summary comes from the ClinGen Evidence Repository: The c.1849G>A (p.Ala617Thr) variant has an allele frequency of 0.04479 (4.5%, 1,076/24,022 alleles) in the African subpopulation of the gnomAD cohort (BA1). 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): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA121991/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.1849G>A | p.Ala617Thr | missense_variant | 12/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.1666G>A | p.Ala556Thr | missense_variant | 11/15 | ||
CDH1 | NM_001317185.2 | c.301G>A | p.Ala101Thr | missense_variant | 12/16 | ||
CDH1 | NM_001317186.2 | c.-117G>A | 5_prime_UTR_variant | 11/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.1849G>A | p.Ala617Thr | missense_variant | 12/16 | 1 | NM_004360.5 | P1 | |
ENST00000563916.1 | n.263+1126C>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes AF: 0.0129 AC: 1969AN: 152098Hom.: 49 Cov.: 31
GnomAD3 exomes AF: 0.00349 AC: 878AN: 251466Hom.: 18 AF XY: 0.00252 AC XY: 342AN XY: 135904
GnomAD4 exome AF: 0.00143 AC: 2097AN: 1461870Hom.: 36 Cov.: 32 AF XY: 0.00127 AC XY: 924AN XY: 727242
GnomAD4 genome AF: 0.0130 AC: 1974AN: 152216Hom.: 49 Cov.: 31 AF XY: 0.0125 AC XY: 929AN XY: 74412
ClinVar
Submissions by phenotype
not specified Benign:8Other:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 29, 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. - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 22, 2015 | - - |
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
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 | PreventionGenetics, part of Exact Sciences | Dec 12, 2016 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Hereditary diffuse gastric adenocarcinoma Benign:6
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 | Invitae | Feb 01, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 07, 2023 | This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. - |
Benign, criteria provided, single submitter | clinical testing | Pathway Genomics | Oct 30, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Counsyl | Mar 23, 2016 | - - |
Hereditary cancer-predisposing syndrome Benign:6
Benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Oct 10, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Feb 14, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 10, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 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. - |
Benign, criteria provided, single submitter | clinical testing | Vantari Genetics | Jan 21, 2016 | - - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 21, 2020 | - - |
not provided Benign:3
Benign, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | CDH1: BP4, BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 27, 2023 | - - |
DIFFUSE GASTRIC AND LOBULAR BREAST CANCER SYNDROME Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2003 | - - |
Endometrial carcinoma Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2003 | - - |
Familial cancer of breast;C0376358:Malignant tumor of prostate;C0476089:Endometrial carcinoma;C0919267:Ovarian neoplasm;C1708349:Hereditary diffuse gastric adenocarcinoma;C4551988:Blepharocheilodontic syndrome 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 25, 2021 | - - |
Breast and/or ovarian cancer Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 26, 2021 | - - |
Malignant tumor of breast Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CDH1 p.Ala617Thr variant was identified in 7 of 540 proband chromosomes (frequency: 0.013) from individuals or families with osteoblastic osteosarcoma, gastric adenocarcinoma, breast cancer and was present in 14 (all in African American) of 716 (516 African American) control chromosomes (frequency: 0.02) from healthy individuals (Choy 2012, El-Husny 2014, Suriano 2003, Valente 2014). The variant was also identified in dbSNP (ID: rs33935154) as With Pathogenic allele, ClinVar (classified as benign by GeneDx, Ambry Genetics, Pathway Genomics, Invitae, Vantari Genetics, Coulsyl; classified as pathogenic by OMIM), Clinvitae (conflicting interpretations of pathogenicity by ClinVar), Cosmic (neutral), databases. The variant was not identified in MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 1211(25 homozygous) of 277184 chromosomes at a frequency of 0.004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 1076 of 24022 chromosomes (freq: 0.045). The p.Ala617 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Cadherin Cadherin-like functional domain increasing the liklihood that it may have clinical significance. Functional analysis by Suriano (2003) identified cells expressing the Ala617Thr mutation showed the same non-invasive behavior as cells expressing wild-type protein. The case study by Lajus (2015) found the variant in a family with no history of diffuse gastric cancer. The daughter diagnosed with in situ breast cancer does not carry the CDH1 mutation. The index case (72 year old) is alive without the evidence of breast or gastric cancer, and is on surveillance. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. - |
CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:1
Benign, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Aug 08, 2023 | The c.1849G>A (p.Ala617Thr) variant has an allele frequency of 0.04479 (4.5%, 1,076/24,022 alleles) in the African subpopulation of the gnomAD cohort (BA1). 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): BA1. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at