rs587782252
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_000465.4(BARD1):c.1868G>A(p.Gly623Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,613,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G623A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000465.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BARD1 | NM_000465.4 | c.1868G>A | p.Gly623Glu | missense_variant | 9/11 | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.1868G>A | p.Gly623Glu | missense_variant | 9/11 | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152078Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251210Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135748
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461754Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19AN XY: 727180
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152078Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74280
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 09, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 17, 2022 | The p.G623E variant (also known as c.1868G>A), located in coding exon 9 of the BARD1 gene, results from a G to A substitution at nucleotide position 1868. The glycine at codon 623 is replaced by glutamic acid, an amino acid with similar properties. This alteration was previously reported in a cohort of 1162 individuals with sarcoma (Ballinger ML et al. Lancet Oncol. 2016 Sep;17:1261-71). In another study, this variant was detected in 1/91 Irish breast cancer patients and 0/77 ethnically matched controls (McVeigh ÚM et al. Ir J Med Sci, 2020 Aug;189:849-864). Homology-directed DNA repair (HDR) assays demonstrated that this alteration has intermediate HDR function (Lee C et al. Hum. Mutat. 2015 Dec;36:1205-14). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 05, 2024 | This missense variant replaces glycine with glutamic acid at codon 623 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function. A functional study has shown that this variant displays defective BRCA1 protein binding ability and results in decreased homology-directed DNA repair activity in mammalian cell-based assays (PMID: 26350354). In a large breast cancer case-control meta-analysis, this variant was identified in 5/60461 cases and 2/53459 unaffected controls (OR=2.21, 95%CI 0.429 to 11.394, p-value=0.459; PMID: 33471991; Leiden Open Variation Database DB-ID BARD1_000145). This variant has been reported in an individual affected with sarcoma (PMID: 27498913). This variant has also been identified in 3/251210 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Familial cancer of breast Uncertain:2Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2024 | - - |
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 07-14-2015 by Lab Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 623 of the BARD1 protein (p.Gly623Glu). This variant is present in population databases (rs587782252, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer and/or sarcoma (PMID: 27498913, 32008151). ClinVar contains an entry for this variant (Variation ID: 142123). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects BARD1 function (PMID: 26350354). 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. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 09, 2024 | Variant summary: BARD1 c.1868G>A (p.Gly623Glu) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251210 control chromosomes. c.1868G>A has been reported in the literature as a VUS in individuals affected with breast cancer and prostate cancer (e.g. McVeigh_2020, Plym_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function, with the variant showing intermediate HDR function (19% of WT) and loss of BRCA1 binding (e.g. Lee_2015). The following publications have been ascertained in the context of this evaluation (PMID: 26350354, 30584090, 32008151, 35079693). ClinVar contains an entry for this variant (Variation ID: 142123). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 26, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 27, 2023 | Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal history of sarcoma or breast cancer (Ballinger et al., 2016; McVeigh et al., 2020); Published functional studies demonstrate intermediate homology-directed repair activity and lack of BRCA1 binding (Lee et al., 2015); This variant is associated with the following publications: (PMID: 27498913, 32008151, 30925164, 17550235, 26350354) - |
Familial ovarian cancer Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BARD1 p.Gly623Glu variant was identified in dbSNP (ID: rs587782252) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, GeneDx, Color, Ambry Genetics and one clinical laboratory). The variant was identified in control databases in 3 of 245976 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 3 of 111450 chromosomes (freq: 0.00003), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The functional study of BARD1 variants has shown the variant defective in homology directed DNA repair and did not bind the BRCA1 protein (Lee 2015). The p.Gly623 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at