Estimating the proportion of pathogenic variants from breast cancer case–control data: Application to calibration of ACMG/AMP variant classification criteria

Abstract

For genes with reliable estimates of disease risk associated with loss-of-function variants, case–control data can be used to estimate the proportion of variants of typical risk effect for defined groups of variants, of relevance for variant classification. A calculation was derived for a maximum likelihood estimate of the proportion of pathogenic variants of typical effect from case–control data and applied to rare variant counts for ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, and RAD51D from published breast cancer studies: BEACCON (5770 familial cases and 5741 controls) and breast cancer risk after diagnostic sequencing (60,466 familial and population-based cases and 53,461 controls)...