rs766173
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_000059.4(BRCA2):c.865A>C(p.Asn289His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0418 in 1,598,150 control chromosomes in the GnomAD database, including 2,166 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N289D) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.865A>C | p.Asn289His | missense_variant | 10/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.865A>C | p.Asn289His | missense_variant | 10/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0409 AC: 6221AN: 152198Hom.: 215 Cov.: 32
GnomAD3 exomes AF: 0.0521 AC: 12475AN: 239502Hom.: 527 AF XY: 0.0548 AC XY: 7094AN XY: 129342
GnomAD4 exome AF: 0.0419 AC: 60573AN: 1445834Hom.: 1948 Cov.: 30 AF XY: 0.0445 AC XY: 31960AN XY: 719010
GnomAD4 genome ? AF: 0.0410 AC: 6240AN: 152316Hom.: 218 Cov.: 32 AF XY: 0.0436 AC XY: 3248AN XY: 74476
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Benign:12
Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Jan 12, 2015 | Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.1049 (Asian), 0.01423 (African), 0.03694 (European), derived from 1000 genomes (2012-04-30). - |
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Mar 15, 2011 | - - |
Benign, criteria provided, single submitter | literature only | Counsyl | Jan 02, 2014 | High frequency in a 1kG or ESP population: 3.7 %. - |
Benign, criteria provided, single submitter | clinical testing | GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited | - | - - |
Benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 09, 2014 | - - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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. - |
not specified Benign:10Other:1
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 27, 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, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneKor MSA | Nov 01, 2017 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency | Apr 18, 2017 | - - |
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 | Eurofins Ntd Llc (ga) | Jun 30, 2015 | - - |
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | #N/A - |
Hereditary breast ovarian cancer syndrome Benign:4
Benign, criteria provided, single submitter | research | Genetics Program, Instituto Nacional de Cancer | Nov 01, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 13, 2014 | - - |
not provided Benign:3
Benign, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 06, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 19, 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 | curation | Sema4, Sema4 | Jan 02, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 04, 2014 | - - |
Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 28, 2022 | - - |
Fanconi anemia complementation group D1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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. - |
Familial cancer of breast Benign:1
Benign, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2017 | - - |
Breast carcinoma Benign:1
Benign, criteria provided, single submitter | clinical testing | Center for Medical Genomics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Faculty of Medicine Ramathibodi Hospital, Mahidol University | Apr 18, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at