ClinVar Genomic variation as it relates to human health

Cys83Arg alters a critical cysteine in the RING domain of BARD1. The residue is completely conserved as cysteine in all sequenced species. The mutation is absent from public databases and co-segregates with breast cancer in one multiplex family. The mutation leads to loss of ubiquitylation of histone 2A on nucleosomes and to defective transcriptional regulation of genes of estrogen metabolism (Stewart 2018)

This missense variant replaces cysteine with arginine at codon 83 of the BARD1 protein. This variant alters one of the highly conserved zinc coordinating residues of the BARD1 ring domain. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein in complex with BRCA1 is deficient at ubiquitylation of nucleosomal histone H2A in vitro (PMID: 29367421; Upadhyay 2019, dissertation, University of Washington). This variant has been reported in an individual affected with familial breast cancer (PMID: 28486781, 29367421). This variant has also been reported in multiple individuals affected with prostate cancer (Color internal data). One of these individuals has a family history of breast cancer and prostate cancer. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

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. Experimental studies have shown that this missense change affects BARD1 function (PMID: 29367421). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 628328). This missense change has been observed in individual(s) with breast cancer (PMID: 28486781, 29367421). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 83 of the BARD1 protein (p.Cys83Arg).

The p.C83R variant (also known as c.247T>C), located in coding exon 3 of the BARD1 gene, results from a T to C substitution at nucleotide position 247. The cysteine at codon 83 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been observed in multiple individuals with a personal and/or family history of breast cancer (Lolas Hamameh S et al. Int J Cancer, 2017 Aug;141:750-756; Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094). Experimental studies suggest this missense change may impact BARD1 function (Stewart MD et al. Proc Natl Acad Sci U S A, 2018 Feb;115:1316-1321). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.