ClinVar Genomic variation as it relates to human health

The BARD1 variant designated as NM_000465.3:c.1977A>G (p.Arg659=) is classified as likely benign. The variant is present in approximately 1 in every 170 individuals with European ancestry (exac.broadinstitute.org), which is more common than cancer risk variants. In one observed family, the allele did not travel with breast cancer in the family, providing additional evidence that the BARD1 p.Arg659= is benign. This variant has been classified as likely benign by other laboratories (ClinVar Variation ID: 127727). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a <1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter BARD1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

Variant summary: BARD1 c.1977A>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing; however ESEfinder predicts binding motif alterations for RNA splicing enhancers. Supporting the prediction of altered binding motifs, a functional study showed that this variant was associated with a transcript lacking exons 2-9 resulting in a very short open reading frame (p.Cys53_Trp635delinsfsX12) in addition to full-length transcript at a ratio of 3.8 (full-length to short; Ratajska_2012), which was not seen in controls. In a recent functional study examining the effect of variant at the cellular level, the authors observed a significant increase of telomere abnormalities (Pilyugin_2017). Pathogenic variants in BARD1 gene confer increased risk of breast and/or ovarian cancer. Monoallelic germline mutations in BARD1 are estimated to confer up to a 3 fold increased risk for breast cancer compared to the general population (PMID: 22264603). Given the unknown clinical effect of this occasional splicing abnormality, the importance of these in vitro studies is unclear. This variant was found in 572/ 279550 control chromosomes (including one homozygous occurrence) at a frequency of 0.002, which is more than 8 times greater than the maximal expected frequency of a pathogenic allele (0.00025) in this gene. Additionally, the observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database and publications is approximately 30.8 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 Ashkenazi Jewish origin. c.1977A>G has been reported in the literature and in one poster from Ambry Genetics in individuals affected with Hereditary Breast and Ovarian Cancer (Ratajska_2012, Ratajska_2015, Pesaran_2013) with a combined OR of 2.76. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

This variant is associated with the following publications: (PMID: 26075229, 32025336, 25994375, 26738429, 26329992, 28030839, 22433386, 21344236, 28821472, 26787654, 30441849, 31142030, 30374176)

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.

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.

BARD1: BP4, BS1, BS2

The BARD1 p.Arg659= variant was identified in 50 of 25,074 proband chromosomes (frequency: 0.002) from individuals or families with basal cell carcinoma and hereditary breast and ovarian cancer and was present in 14 of 9414 control chromosomes (frequency: 0.001) from healthy individuals (Suszynska 2019, Cho 2018). The variant was identified in dbSNP (rs147215925) as “with other allele” and ClinVar (classified as likely benign by GeneDx, Ambry Genetics, Mendelics and 4 other submitters, benign by Invitae, Color and Quest Diagnostics and uncertain significance by Integrated Genetics and Prevention Genetics). The variant was identified in control databases in 576 of 282,800 chromosomes (1 homozygous) at a frequency of 0.002 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: Ashkenazi Jewish in 81 of 10,366 chromosomes (freq: 0.008), Other in 24 of 7216 chromosomes (freq: 0.003), European in 398 of 129,128 chromosomes (freq: 0.003), Finnish in 33 of 25,118 chromosomes (freq: 0.001), Latino in 30 of 35,438 chromosomes (freq: 0.0008), African in 9 of 24,968 chromosomes (freq: 0.0004), South Asian in 1 of 30,612 chromosomes (freq: 0.00003), while the variant was not observed in the East Asian population. The p.Arg659= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs at a non-highly conserved nucleotide 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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).