rs147215925
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_000465.4(BARD1):c.1977A>G(p.Arg659Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,613,972 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0022 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0032 ( 11 hom. )
Consequence
BARD1
NM_000465.4 synonymous
NM_000465.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.699
Genes affected
BARD1 (HGNC:952): (BRCA1 associated RING domain 1) This gene encodes a protein which interacts with the N-terminal region of BRCA1. In addition to its ability to bind BRCA1 in vivo and in vitro, it shares homology with the 2 most conserved regions of BRCA1: the N-terminal RING motif and the C-terminal BRCT domain. The RING motif is a cysteine-rich sequence found in a variety of proteins that regulate cell growth, including the products of tumor suppressor genes and dominant protooncogenes. This protein also contains 3 tandem ankyrin repeats. The BARD1/BRCA1 interaction is disrupted by tumorigenic amino acid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression. This protein may be the target of oncogenic mutations in breast or ovarian cancer. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
Variant 2-214730435-T-C is Benign according to our data. Variant chr2-214730435-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127727.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=7, Likely_benign=10}. Variant chr2-214730435-T-C is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=0.699 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00223 (340/152282) while in subpopulation NFE AF= 0.00419 (285/68020). AF 95% confidence interval is 0.00379. There are 3 homozygotes in gnomad4. There are 149 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 340 AD gene.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00223 AC: 340AN: 152164Hom.: 3 Cov.: 32
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GnomAD3 exomes AF: 0.00197 AC: 494AN: 251398Hom.: 1 AF XY: 0.00175 AC XY: 238AN XY: 135872
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GnomAD4 exome AF: 0.00323 AC: 4728AN: 1461690Hom.: 11 Cov.: 30 AF XY: 0.00310 AC XY: 2256AN XY: 727142
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GnomAD4 genome 0.00223 AC: 340AN: 152282Hom.: 3 Cov.: 32 AF XY: 0.00200 AC XY: 149AN XY: 74466
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:22
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:6
| Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2025 | BARD1: BP4, BS1, BS2 - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 06, 2021 | This variant is associated with the following publications: (PMID: 26075229, 32025336, 25994375, 26738429, 26329992, 28030839, 22433386, 21344236, 28821472, 26787654, 30441849, 31142030, 30374176) - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 13, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Familial cancer of breast Uncertain:1Benign:6
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 04, 2025 | - - |
| Likely benign, criteria provided, single submitter | research | University of Washington Department of Laboratory Medicine, University of Washington | Mar 28, 2018 | The BARD1 variant designated as NM_000465.3:c.1977A>G (p.Arg659=) is classified as likely benign. The variant is present in approximately 1 in every 170 individuals with European ancestry (exac.broadinstitute.org), which is more common than cancer risk variants. In one observed family, the allele did not travel with breast cancer in the family, providing additional evidence that the BARD1 p.Arg659= is benign. This variant has been classified as likely benign by other laboratories (ClinVar Variation ID: 127727). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a <1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter BARD1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. - |
| Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 24, 2023 | This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. - |
| Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 24, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Nov 09, 2017 | - - |
Hereditary cancer-predisposing syndrome Benign:4
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 30, 2020 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 09, 2021 | 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jul 12, 2017 | - - |
| Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 15, 2020 | - - |
not specified Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 16, 2018 | Variant summary: BARD1 c.1977A>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing; however ESEfinder predicts binding motif alterations for RNA splicing enhancers. Supporting the prediction of altered binding motifs, a functional study showed that this variant was associated with a transcript lacking exons 2-9 resulting in a very short open reading frame (p.Cys53_Trp635delinsfsX12) in addition to full-length transcript at a ratio of 3.8 (full-length to short; Ratajska_2012), which was not seen in controls. In a recent functional study examining the effect of variant at the cellular level, the authors observed a significant increase of telomere abnormalities (Pilyugin_2017). Pathogenic variants in BARD1 gene confer increased risk of breast and/or ovarian cancer. Monoallelic germline mutations in BARD1 are estimated to confer up to a 3 fold increased risk for breast cancer compared to the general population (PMID: 22264603). Given the unknown clinical effect of this occasional splicing abnormality, the importance of these in vitro studies is unclear. This variant was found in 572/ 279550 control chromosomes (including one homozygous occurrence) at a frequency of 0.002, which is more than 8 times greater than the maximal expected frequency of a pathogenic allele (0.00025) in this gene. Additionally, the observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database and publications is approximately 30.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in BARD1 causing Hereditary Breast and Ovarian Cancer phenotype (0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.1977A>G has been reported in the literature and in one poster from Ambry Genetics in individuals affected with Hereditary Breast and Ovarian Cancer (Ratajska_2012, Ratajska_2015, Pesaran_2013) with a combined OR of 2.76. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
| 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 | Genetic Services Laboratory, University of Chicago | Jul 21, 2020 | - - |
Breast and/or ovarian cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 01, 2023 | - - |
BARD1-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 16, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Malignant tumor of breast Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BARD1 p.Arg659= variant was identified in 50 of 25,074 proband chromosomes (frequency: 0.002) from individuals or families with basal cell carcinoma and hereditary breast and ovarian cancer and was present in 14 of 9414 control chromosomes (frequency: 0.001) from healthy individuals (Suszynska 2019, Cho 2018). The variant was identified in dbSNP (rs147215925) as “with other allele” and ClinVar (classified as likely benign by GeneDx, Ambry Genetics, Mendelics and 4 other submitters, benign by Invitae, Color and Quest Diagnostics and uncertain significance by Integrated Genetics and Prevention Genetics). The variant was identified in control databases in 576 of 282,800 chromosomes (1 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 81 of 10,366 chromosomes (freq: 0.008), Other in 24 of 7216 chromosomes (freq: 0.003), European in 398 of 129,128 chromosomes (freq: 0.003), Finnish in 33 of 25,118 chromosomes (freq: 0.001), Latino in 30 of 35,438 chromosomes (freq: 0.0008), African in 9 of 24,968 chromosomes (freq: 0.0004), South Asian in 1 of 30,612 chromosomes (freq: 0.00003), while the variant was not observed in the East Asian population. The p.Arg659= 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. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at