2-214745838-C-T
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000465.4(BARD1):c.1694G>A(p.Arg565His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,614,046 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00022 ( 3 hom. )
Consequence
BARD1
NM_000465.4 missense
NM_000465.4 missense
Scores
4
15
Clinical Significance
Conservation
PhyloP100: 2.85
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 -13 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.016323835).
BP6
Variant 2-214745838-C-T is Benign according to our data. Variant chr2-214745838-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127721.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=9, Uncertain_significance=3}.
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000219 (320/1461752) while in subpopulation SAS AF= 0.00176 (152/86254). AF 95% confidence interval is 0.00153. There are 3 homozygotes in gnomad4_exome. There are 190 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 20 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BARD1 | NM_000465.4 | c.1694G>A | p.Arg565His | missense_variant | 8/11 | ENST00000260947.9 | NP_000456.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BARD1 | ENST00000260947.9 | c.1694G>A | p.Arg565His | missense_variant | 8/11 | 1 | NM_000465.4 | ENSP00000260947.4 |
Frequencies
GnomAD3 genomes 0.000131 AC: 20AN: 152176Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000414 AC: 104AN: 251320Hom.: 0 AF XY: 0.000501 AC XY: 68AN XY: 135824
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GnomAD4 exome AF: 0.000219 AC: 320AN: 1461752Hom.: 3 Cov.: 31 AF XY: 0.000261 AC XY: 190AN XY: 727176
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GnomAD4 genome 0.000131 AC: 20AN: 152294Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74468
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:13
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial cancer of breast Uncertain:1Benign:4
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
| Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
| Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 26, 2024 | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. - |
| Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Sep 16, 2019 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: No criteria apply. - |
Hereditary cancer-predisposing syndrome Benign:4
| Benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jun 22, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 03, 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 | Color Diagnostics, LLC DBA Color Health | Oct 02, 2015 | - - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | May 30, 2021 | - - |
not specified Uncertain:1Benign:2
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 17, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 17, 2019 | Variant summary: BARD1 c.1694G>A (p.Arg565His) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 251836 control chromosomes, predominantly at a frequency of 0.0022 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 9 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 South Asian origin. The variant, c.1694G>A, has been reported in the literature in individuals affected with breast and/or ovarian Cancer (Ramus_2015, Gorringe_2008, Yadav_2016, Tung_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication, Adamovich_2019, reported the HDR activity of the variant protein was 60% of normal. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS (n=5), Likely benign (n=1)). Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided Uncertain:1Benign:2
| 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, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | BARD1: PM5, BP4, BS1 - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 09, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast or ovarian cancer (Gorringe 2008, Ramus 2015, Tung 2015); Published functional studies demonstrate no damaging effect: HDR similar to wild type; This variant is associated with the following publications: (PMID: 17972171, 23056176, 27621404, 26315354, 27878467, 25186627, 30925164) - |
Malignant tumor of breast Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BARD1 p.Arg565His variant was identified in 6 of 7136 proband chromosomes (frequency: 0.0008) from individuals or families with breast cancer (familial, sporadic or BRCA1/2 negative) or ovarian cancer and was not identified in 7490 control chromosomes from healthy individuals (Gorringe 2008, Ramus 2015, Yadav 2017). The variant was also identified in dbSNP (ID: rs146946984) “With Uncertain significance allele”, ClinVar (classified as likely benign by Invitae and Integrated Genetics; and as uncertain significance by GeneDx, Ambry Genetics, and three other submitters). The variant was identified in control databases in 103 of 277048 chromosomes at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 71 of 30780 chromosomes (freq: 0.002), Ashkenazi Jewish in 13 of 10148 chromosomes (freq: 0.001), Other in 1 of 6458 chromosomes (freq: 0.0002), Latino in 3 of 34418 chromosomes (freq: 0.00009), European Non-Finnish in 13 of 126568 chromosomes (freq: 0.0001), and East Asian in 2 of 18866 chromosomes (freq: 0.0001), while it was not observed in the African or Finnish populations. The p.Arg565 residue is conserved in mammals but not in more distantly related organisms; however, four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood that the His variant impacts the protein; 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) 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. This variant is classified as a variant of uncertain significance. - |
BARD1-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 03, 2020 | 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). - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
D;D;T;T;.
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.;.;.;.
MutationTaster
Benign
D;N
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;.;N
REVEL
Benign
Sift
Benign
T;.;.;.;D
Sift4G
Uncertain
D;D;T;T;T
Polyphen
B;.;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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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