2-214752538-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM1PP3BP6BS2_Supporting
The NM_000465.4(BARD1):c.1586G>A(p.Arg529Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R529G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000465.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BARD1 | NM_000465.4 | c.1586G>A | p.Arg529Gln | missense_variant | 7/11 | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.1586G>A | p.Arg529Gln | missense_variant | 7/11 | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152022Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000139 AC: 35AN: 251276Hom.: 1 AF XY: 0.000125 AC XY: 17AN XY: 135802
GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461158Hom.: 0 Cov.: 30 AF XY: 0.0000344 AC XY: 25AN XY: 726920
GnomAD4 genome AF: 0.0000592 AC: 9AN: 152022Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7AN XY: 74254
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | BARD1: PP3, BS1 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 16, 2023 | PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 30, 2023 | In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with breast, ovarian, or colon cancer, and also in unaffected controls (Young et al., 2016; Yurgelun et al., 2017; Kwong et al., 2020; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 25922291, 26787654, 28135145, 33471991, 32068069, 18480049, 31371347) - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 05, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 16, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 12, 2022 | 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. - |
Familial cancer of breast Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 06, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 29, 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]. - |
Familial pancreatic carcinoma Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BARD1 p.Arg529Gln variant was identified in 1 of 2116 proband chromosomes (frequency: 0.0005) from individuals or families with colorectal cancer (Yurgelun 2017) and was also identified in a study which included 1297 breast cancer cases and 1121 controls, however the frequency of this variant was not specified (Young 2016). The variant was also identified in dbSNP (ID: rs753479021) as "With Uncertain significance allele", and in ClinVar and Clinvitae (classified as likely benign by Invitae and as uncertain significance by Ambry Genetics, GeneDx, Color and Counsyl). The variant was not identified in the COSMIC or MutDB databases. The variant was identified in control databases in 37 of 276996 chromosomes at a frequency of 0.0001 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: European Non-Finnish in 3 of 126562 chromosomes (freq: 0.00002), East Asian in 34 of 18864 chromosomes (freq: 0.002); it was not observed in the African, Other, Latino, Ashkenazi Jewish, Finnish, and South Asian populations. The variant was observed in the Exome Aggregation Consortium database (August 8th 2016) in the East Asian population in 19 of 8650 chromosomes (freq: 0.002) including 1 homozygous individual. The p.Arg529 residue is 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 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 29, 2021 | Variant summary: BARD1 c.1586G>A (p.Arg529Gln) results in a 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 0.00014 in 251276 control chromosomes, predominantly at a frequency of 0.0017 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 7 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 East Asian origin. c.1586G>A has been reported in the literature as a VUS in settings of multigene cancer panel testing among affected individuals (example, Yurgelun_2017, Kwong_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2, VUS, n=4). Based on the evidence outlined above, the variant was classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at