2-214728728-C-T
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The ENST00000260947.9(BARD1):c.2282G>A(p.Ser761Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,614,198 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S761G) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 2 hom. )
Consequence
BARD1
ENST00000260947.9 missense
ENST00000260947.9 missense
Scores
2
17
Clinical Significance
Conservation
PhyloP100: 3.47
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 -9 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.008288771).
BP6
Variant 2-214728728-C-T is Benign according to our data. Variant chr2-214728728-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127735.We mark this variant Likely_benign, oryginal submissions are: {Benign=8, Uncertain_significance=4, Likely_benign=9}. Variant chr2-214728728-C-T is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 223 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BARD1 | NM_000465.4 | c.2282G>A | p.Ser761Asn | missense_variant | 11/11 | ENST00000260947.9 | NP_000456.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BARD1 | ENST00000260947.9 | c.2282G>A | p.Ser761Asn | missense_variant | 11/11 | 1 | NM_000465.4 | ENSP00000260947 | P2 |
Frequencies
GnomAD3 genomes 0.00147 AC: 223AN: 152200Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00170 AC: 426AN: 251230Hom.: 1 AF XY: 0.00168 AC XY: 228AN XY: 135768
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GnomAD4 exome AF: 0.00108 AC: 1586AN: 1461880Hom.: 2 Cov.: 32 AF XY: 0.00106 AC XY: 770AN XY: 727242
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GnomAD4 genome 0.00146 AC: 223AN: 152318Hom.: 1 Cov.: 32 AF XY: 0.00172 AC XY: 128AN XY: 74494
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:18
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial cancer of breast Uncertain:1Benign:5
| Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Oct 26, 2017 | - - |
| Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 24, 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. 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]. - |
| 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Uncertain significance. - |
| Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 09, 2022 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
not provided Uncertain:1Benign:4
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 28, 2016 | Variant summary: The BARD1 c.2282G>A (p.Ser761Asn) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 222/129722 control chromosomes (3 homozygotes), predominantly observed in the European (Finnish) subpopulation in ExAC at a frequency of 0.0098366 (65/6608). This frequency is about 45 times the estimated maximal expected allele frequency of a pathogenic BARD1 variant (0.0002188), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. This variant has been reported in affected individuals with comparable MAF as in tested controls. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign, without evidence for independent evaluation. Functional studies showd that variant may lead to defective BARD1 function in growth suppression and apoptosis, however, this variant is shown not to affect the HDR activity. Taken all lines of evidence together, this variant is classified as likely benign until more information becomes available. - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | BARD1: BP4, BS1 - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 23, 2018 | This variant is associated with the following publications: (PMID: 26787654, 26976419, 11807980, 28335968, 25980754, 18089818, 23056176, 17972171, 25288723, 17848578, 20077502, 16061562, 22006311, 26738429, 26350354, 9798686, 17550235, 9425226, 26898890, 26517685, 31159747) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 21, 2022 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:4
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
| Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 09, 2020 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 19, 2014 | - - |
| Benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Oct 18, 2022 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 23, 2018 | 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. - |
not specified Benign:3
| Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 11, 2017 | - - |
| Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 08, 2020 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Hereditary cancer Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Nov 20, 2014 | - - |
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 | May 23, 2023 | - - |
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.Ser761Asn variant was identified in 2 of 1220 proband chromosomes (frequency: 0.002) from individuals or families with breast, ovarian, uterine and endometrial cancers, and was present in 2 of 966 control chromosomes (frequency: 0.002) from healthy individuals (De Brakeleer 2010, Gorringe 2008, Thai 1998). The variant was also identified in dbSNP (ID: rs142155101) as “With Uncertain significance allele”, ClinVar database (1x as benign by Invitae; 3x as likely benign by GeneDx, Ambry Genetics, Illumina; 1x as uncertain significance by CMGUMCL), Clinvitae database (classified as benign by Invitae; classified as likely benign and uncertain significance by ClinVar), MutDB, Zhejiang Colon Cancer Database (LOVD), databases. This variant was identified in the genome Aggregation Database (Genome Aggregation Consortium Feb 27, 2017) in 484 (3 homozygous) of 276958 chromosomes (freq. 0.002), in the following populations: Finnish in 247 of 25792 (2 homozygous) chromosomes (freq. 0.0095), Ashkenazi Jewish in 34 of 10146 chromosomes (freq. 0.0033), European in 189 of 126482 (1 homozygous) chromosomes (freq. 0.0015), other in 7 of 6460 chromosomes (freq. 0.001), Latino in 6 of 34406 chromosomes (freq. 0.00017), African in 1 of 24028 chromosomes (freq. 0.00004), increasing the likelihood this could be a low frequency benign variant. The variant p.Ser761Asn has been identified as cancer-associated missense mutation in breast and uterine cancers (Birrane 2007). This variant was also identified in a screen of 150 sporadic tumors and was not present in normal cells of the patients, indicating that they arose somatically during tumor development (Laufer 2007). The p.Ser761Asn variant was also identified as a somatic variant in endometrial cancer patient at age 8 with associated LOH (Thai 1998).The p.Ser761Asn variant is identified as putative disease associated allele (Sauer 2005).The p.Ser761 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time but we would lean towards a more benign role for this variant. It is classified as likely benign. - |
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
Uncertain
D
LIST_S2
Benign
T;D;D;D;T;.
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;.;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;.;.;.
REVEL
Benign
Sift
Benign
T;.;.;.;.;.
Sift4G
Benign
T;T;T;T;T;T
Polyphen
B;.;.;.;.;.
Vest4
MVP
MPC
ClinPred
T
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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