Comparison of MPT Series with Other Datasets
To consider how the tumor combinations in our series differed from those in the general population, we compared combination frequencies in our MPT data with a previously analyzed dataset from the East Anglia Cancer Registry (2009–2014; population size ∼5.5 million). Registry data recorded individuals with two cancer (or central nervous system [CNS] tumor) diagnoses before the age of 60 years and only included tumors occurring before that age. Consequently, only combinations in MPT data of two malignant (or CNS) tumors occurring before 60 years of age were considered for this comparison.
To compare detection rates of loss-of-function variants in our cohort with a large-scale WGS dataset unselected for neoplastic phenotypes, we interrogated gnomAD18 (data downloaded in February 2018) for variants occurring in the same set of 83 genes. Only truncating or splice-site variants were considered for comparison purposes because these are less likely to be false positives and made up 52/63 (82.5%) (see Results) of the P/LP variants in our cohort. Variants extracted from gnomAD were filtered and assessed in the same manner as those occurring in the MPT cohort. The frequency of variants assessed as P/LP was also calculated for males and females, and the sex distribution of individuals in the gnomAD dataset (55.3% male and 44.6% female) was estimated with mean allele count across all positions in the gnomAD VCF file of chromosomes 1–22. In order to estimate gnomAD P/LP variant frequency as though the sex distribution was equivalent to that in the MPT series (23% male and 77% female), we applied the sex-specific frequency to the estimated total number of gnomAD females (n = 6,929) and a reduced number of males (n = 2,064) that would achieve the desired proportion. We then summed the respective allele-frequency estimates to provide a figure for comparison with the MPT series.