Every single-nucleotide change compatible with life is present in the human population today. Understanding these rare human variants defines an extraordinary challenge for genetics and medicine. The new clinical practice of sequencing many genes for hereditary cancer risk has illustrated the utility of clinical next-generation sequencing in adults, identifying more medically actionable variants than single-gene testing. However, it has also revealed a linear relationship between the length of DNA evaluated and the number of rare ‘variants of uncertain significance’ reported. We propose that careful approaches to phenotype-genotype inference, distinguishing between diagnostic and screening intent, in conjunction with expanded use of family-scale genetics studies as a source of information on family-specific variants, will reduce variants of uncertain significance reported to patients.
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