Retained variants were subsequently excluded if their putative pathogenicity could be refuted by one of the following criteria: (1) a predicted protein-truncating variant for which there was at least two-star evidence of a benign or uncertain effect in ClinVar; (2) a predicted protein-truncating variant in a proto-oncogene in a list compiled on the basis of a literature review1 (constitutional cancer-predisposing variants in proto-oncogenes are associated with gain-of-function variants, so truncation of the protein product is unlikely to increase tumor risk), (3) a predicted protein-truncating variant affecting <5% of the canonical transcript (according to the LOFTEE VEP plugin), (4) a variant affecting a gene associated with only recessive tumor predisposition (as defined by a literature review1, 16, 23) unless an individual appeared to harbor two filtered variants in the same gene, and (5) a variant with HGMD DM status or that exceeded the CADD score threshold and had at least two-star evidence of a benign or uncertain clinical effect or one-star evidence if there were multiple submissions without a P/LP assertion.