Thousands of genetic variants of BRCA1 have been more accurately classified in terms of their function in a paper published online this week in Nature. These functional scores could have clinical implications for the interpretation of genetic tests for risk of breast and ovarian cancer.
BRCA1 is a human tumour-suppression gene, the loss of function of which is associated with a predisposition for early-onset breast and ovarian cancer. Although thousands of BRCA1 variants have been identified, many of them are classified as ‘variants of uncertain significance’, which makes assessing cancer risk challenging.
One method of addressing this uncertainty is to test whether the expression of a variant fulfils its function of restoring DNA repair, which is integral to tumour suppression. Jay Shendure and colleagues use genome editing to assess the function of nearly 4,000 single-nucleotide variants (SNVs) across 13 exons that are critical to the function of BRCA1. The authors measure subsequent cell survival in 20 million haploid human (HAP1) cells and identify around 300 SNVs that disrupt expression, as well as over 400 missense mutation SNVs (which change the amino acid sequence of proteins) that are actually non-functional. These functional scores closely correlate with established clinical assessments of pathogenic or benign variants.
The authors note that using the HAP1 cell line may not be the most physiologically appropriate model compared to other cell lines; however, the high correlations with clinical assessments validate the data. They highlight the value of function scores in classifying variants and suggest these findings will have immediate clinical use in interpreting BRCA1 genetic screening.