Another possibility is that tumors can occur coincidentally in the presence of a pathogenic constitutional CPG variant. Variants might be considered causative in some contexts or tissues (and would therefore be likely to pass our filtering and assessment) but potentially not in others. For example, an in-frame FH insertion (c.1433−1434insAAA [p.Lys477_Asn478insLys] [Ensembl: ENST00000366560; GenBank: NM_000143.3]) was identified in three individuals, none of whom had been diagnosed with typical hereditary leiomyoma or RCC tumors. This variant causes recessively inherited fumarate hydratase deficiency (MIM: 606812) and has been demonstrated to disrupt enzyme activity.49 However, its significance to cancer predisposition in the heterozygous state is less well defined.