rs145009419
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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.668A>G(p.Glu223Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,591,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.00025 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00018 ( 0 hom. )
Consequence
BARD1
NM_000465.4 missense
NM_000465.4 missense
Scores
19
Clinical Significance
Conservation
PhyloP100: 0.190
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=0.04667273).
BP6
Variant 2-214781206-T-C is Benign according to our data. Variant chr2-214781206-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127743.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Likely_benign=7}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000249 (38/152324) while in subpopulation NFE AF= 0.000485 (33/68030). AF 95% confidence interval is 0.000354. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 38 AD gene.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000250 AC: 38AN: 152206Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000161 AC: 37AN: 229148Hom.: 0 AF XY: 0.000169 AC XY: 21AN XY: 123902
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GnomAD4 exome AF: 0.000185 AC: 266AN: 1439510Hom.: 0 Cov.: 34 AF XY: 0.000171 AC XY: 122AN XY: 715320
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GnomAD4 genome 0.000249 AC: 38AN: 152324Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74490
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:11Benign:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial cancer of breast Uncertain:5Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 24, 2023 | 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]. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 223 of the BARD1 protein (p.Glu223Gly). This variant is present in population databases (rs145009419, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer or clinical features of Lynch syndrome (PMID: 25186627, 25980754, 26976419). ClinVar contains an entry for this variant (Variation ID: 127743). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 30925164). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Mar 22, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 07, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
not specified Uncertain:2Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 18, 2023 | Variant summary: BARD1 c.668A>G (p.Glu223Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 229148 control chromosomes, predominantly at a frequency of 0.00032 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in BARD1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant has also been found in 5/7325 European American women over the age of 70 with no personal history of cancer (FLOSSIES database). c.668A>G has been reported in the literature in individuals with suspected Lynch syndrome, affected with breast cancer and endometrial cancer without strong evidence of causality (Tung_2015, Yurgelun_2015, Ring_2016), as well as in individuals with family histories suggesting Hereditary Breast And Ovarian Cancer (Caminsky_2016) and breast cancer (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (CHEK2 c.1100del , p.Thr367Metfs*15), providing supporting evidence for a benign role. Functional assays using homology directed repair of two non-functional GFP coding sequences showed the variant had similar HDR activity as wild-type BARD1, showing no damaging effect of this variant (Adamovich_2019). The following publications have been ascertained in the context of this evaluation (PMID: 25980754, 23056176, 25186627, 26898890, 27443514, 30925164, 33471991). 14 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 30, 2021 | DNA sequence analysis of the BARD1 gene demonstrated a sequence change, c.668A>G, in exon 4 that results in an amino acid change, p.Glu223Gly. This sequence change has been described in the gnomAD database with frequency of 0.033% in the non-Finnish European subpopulation (dbSNP rs145009419). The p.Glu223Gly change affects a moderately conserved amino acid residue located in a domain of the BARD1 protein that is not known to be functional. The p.Glu223Gly substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in individuals who underwent germline genetic testing based on a personal history of breast cancer or a Lynch syndrome-associated cancer (PMID: 26976419, 25980754). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Glu223Gly change remains unknown at this time. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
not provided Uncertain:1Benign:2
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 28, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate homology-directed repair activity similar to wild-type (Adamovich 2019); This variant is associated with the following publications: (PMID: 23056176, 27742771, 25980754, 26976419, 26898890, 27443514, 28873162, 25186627, 30925164, 27535533) - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | BARD1: BP4, BS1:Supporting, BS3:Supporting - |
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 14, 2020 | - - |
Hereditary cancer-predisposing syndrome Benign:3
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 18, 2020 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 15, 2015 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 27, 2020 | 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. - |
Breast and/or ovarian cancer Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 14, 2023 | - - |
BARD1-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 17, 2024 | The BARD1 c.668A>G variant is predicted to result in the amino acid substitution p.Glu223Gly. This variant has been identified in an individual suspected of Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754). This variant was also identified in individuals with breast and/or ovarian cancer (Table A2, Tung et al. 2016. PubMed ID: 26976419; Table S9, Caminsky et al. 2016. PubMed ID: 26898890), endometrial cancer (Table S2, Ring et al. 2016. PubMed ID: 27443514), as well as in an individual with advanced cancer (type unspecified) (eTable, Mandelker et al. 2017. PubMed ID: 28873162). In the aforementioned studies, no evidence was provided to determine the pathogenicity of this variant. This variant has been observed with a minor allele frequency of up to 0.033% in a large population database, and is reported in ClinVar with interpretations ranging from likely benign to variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127743/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
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.Glu223Gly variant was identified in 2 of 3496 proband chromosomes (frequency 0.00057) from American individuals with Lynch syndrome-associated cancer and/or polyps and breast cancer (Yurgelun_2015_25980754, Tung_2016_26976419). The variant was also identified in dbSNP (ID: rs145009419) as “With Uncertain significance allele”, ClinVar and Clinvitae (4x classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, and Fulgent Genetics), and the Zhejiang Colon Cancer Database (1 entry, pathogenicity unknown). The variant was not identified in the COSMIC or MutDB databases. The variant was identified in control databases in 41 of 255258 chromosomes at a frequency of 0.00016 increasing the likelihood this could be a low frequency variant in certain populations (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 23436 chromosomes (freq: 0.000043), European Non-Finnish in 38 of 120160 chromosomes (freq: 0.00032), European Finnish in 2 of 25186 chromosomes (freq: 0.00008); it was not observed in the “Other”, Latino, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Glu223Gly 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 of impact to the protein, but this information is not predictive enough to rule out 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. This variant is classified as a variant of uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.
PrimateAI
Benign
T
PROVEAN
Benign
N;.
REVEL
Benign
Sift
Benign
T;.
Sift4G
Benign
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