rs543304
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_000059.4(BRCA2):c.3807T>C(p.Val1269=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 1,589,028 control chromosomes in the GnomAD database, including 25,419 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. V1269V) has been classified as Benign.
Frequency
Genomes: 𝑓 0.18 ( 2553 hom., cov: 33)
Exomes 𝑓: 0.18 ( 22866 hom. )
Consequence
BRCA2
NM_000059.4 synonymous
NM_000059.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.00500
Genes affected
BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]
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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=-0.87).
BP6
Variant 13-32338162-T-C is Benign according to our data. Variant chr13-32338162-T-C is described in ClinVar as [Benign]. Clinvar id is 126022.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338162-T-C is described in Lovd as [Likely_benign]. Variant chr13-32338162-T-C is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.005 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.3807T>C | p.Val1269= | synonymous_variant | 11/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.3807T>C | p.Val1269= | synonymous_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes 0.181 AC: 27533AN: 152002Hom.: 2552 Cov.: 33
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GnomAD3 exomes AF: 0.175 AC: 40549AN: 232236Hom.: 3594 AF XY: 0.172 AC XY: 21589AN XY: 125672
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GnomAD4 exome AF: 0.176 AC: 253327AN: 1436908Hom.: 22866 Cov.: 35 AF XY: 0.174 AC XY: 123845AN XY: 713570
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GnomAD4 genome 0.181 AC: 27538AN: 152120Hom.: 2553 Cov.: 33 AF XY: 0.179 AC XY: 13289AN XY: 74394
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ClinVar
Significance: Benign
Submissions summary: Benign:30
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Benign:10
| 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 0.1836 (Asian), 0.1972 (African), 0.1794 (European), derived from 1000 genomes (2012-04-30). - |
| Benign, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Apr 12, 1999 | - - |
| Benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
| 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 | literature only | Counsyl | Jan 02, 2014 | High frequency in a 1kG or ESP population: 18.7 %. - |
| Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
| Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Mar 17, 2011 | - - |
| Benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
| Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 10, 2014 | - - |
not specified Benign:8
| Benign, criteria provided, single submitter | clinical testing | Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency | Apr 18, 2017 | - - |
| Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | #N/A - |
| Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency - |
| Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 05, 2016 | - - |
| Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneKor MSA | Nov 01, 2017 | - - |
| Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Hereditary breast ovarian cancer syndrome Benign:4
| 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 | research | Genetics Program, Instituto Nacional de Cancer | Nov 01, 2021 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 20, 2013 | - - |
not provided Benign:3
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 30, 2023 | - - |
| Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
| Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 28, 2016 | - - |
Hereditary cancer-predisposing syndrome Benign:3
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 31, 2015 | - - |
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 21, 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 | Dec 09, 2019 | - - |
Fanconi anemia complementation group D1 Benign:1
| 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. - |
Familial cancer of breast Benign:1
| Benign, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2017 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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