Accurate classification of almost 4,000 SNVs in BRCA1 gene : An example of “saturation genome-editing”

The breast cancer susceptibility gene BRCA1, was first identified and named in 1994. Initially it was declared “THE gene that causes breast cancer” –– but then, shortly thereafter, it became clear that some mutations in this gene contribute ~5% to the overall risk of breast cancer and that certain ethnic groups exhibit a higher frequency than others for these deleterious mutations. For example, there are two clearly deleterious mutations in the BRCA1 gene that are seen at much higher rates in persons of Ashkenazi Jewish ancestry. Ashkenazi women with a mutated BRCA1 or BRCA2 gene have a lifetime risk of between 36% and 85% of developing breast cancer by age 70, whereas the average woman in the U.S. has ~12% risk of developing breast cancer over a 90-year life span. [The BRCA1 and BRCA2 genes encode proteins essential for DNA repair; abnormal copies (alleles) of either of these genes code for proteins which cause that person to be more susceptible to breast (also ovarian) cancer. BRCA1 mutations are responsible for ~40% of ALL INHERITED breast cancers and more than 80% of inherited ovarian cancers.]

BRCA1 is a large gene –– spanning ~81,000 DNA bases on human chromosome 17, and consisting of 24 exons, 22 of which exons encode the BRCA1 phosphoprotein. To make things even more complicated, almost 4,000 mutations [single-nucleotide variants (SNVs)] have now been reported in and near this gene. Which SNVs contribute to causing cancer, and which do not? Authors [see attached article and editorial] used an innovative laboratory-based approach to assess the individual effect of thousands of SNVs across protein-coding regions of BRCA1. As a pivotal tumor suppressor gene, BRCA1 mutations that prevent normal DNA repair lead to death of human HAP1 cultured cells (which represent a near-haploid cell line derived from a male chronic myelogenous leukemia patient).

Authors [see attached] employed “saturation-genome-editing” to assay 96.5% of all possible SNVs in 13 exons that are known to encode functionally critical domains of the BRCA1 protein. Functional effects for nearly 4,000 SNVs were bimodally distributed and almost perfectly concordant with established assessments of pathogenicity. More than 400 non-functional missense SNVs were identified, as well as ~300 SNVs that disrupted expression. Authors predict these data will be immediately useful for clinical interpretations of BRCA1 variants, and that this saturation-genome-editing approach can be extended to overcome the challenge of variants of uncertain significance in additional clinically actionable genes –– which, as every geneticist knows, are always polyallelic (i.e. there are many SNVs; some are detrimental, but many are not).

DwN

Nature 11 Oct 2o18; 562: 217–222 [article] & 201–202 [News’N’Views]

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