SV analysis revealed six potentially pathogenic variants in 440 (1.4%) probands (Table 4), two of whom had previously been diagnosed with tumors typically associated with variants in the relevant gene. An additional two had no associated tumor but a family history of such tumors in a first-degree relative (colorectal cancer at age 56 years for the individual with a SMAD4 translocation and renal cell carcinoma at age 69 for the individual with the TSC1 duplication). One individual with an inversion of PTEN exon 7 had been diagnosed with breast cancer at age 45 years and had a strong family history of this tumor, which had occurred in her sister (age 57 years), mother (age 57 years), and maternal cousin (age 49 years). The proband’s sister had also been diagnosed with a borderline ovarian mucinous tumor and nasal basal cell carcinoma at 46 and 57 years of age, respectively, but WGS did not detect the PTEN inversion in her sample. Another individual had previously been investigated with germline FH sequencing after the diagnosis of multiple cutaneous leiomyomas and a family history of a first-degree relative undergoing a hysterectomy for uterine leiomyomas. SV analysis revealed a whole-gene deletion of FH.
Table 4 Structural Variants Passing Filtering Steps
Gene Chr Predicted Start Predicted End Algorithm(s) Predicted Consequence after IGV Review Phenotype (Age at Diagnosis) Genes Tested by Clinical Services Year Consulted
FLCN 17 1,7136,696 (Manta), 1,7137,867 (Canvas) 17,134,310 (Manta), 17,134,474 (Canvas) Canvas and Manta deletion of exon 2 breast (46 years) and pulmonary lymphangioleiomyomatosis (47 years) information unavailable unknown
PTEN 10 89,719,837 89,713,996 Manta inversion of exon 7 breast (45 years)a BRCA1 and BRCA2 (single gene) unknown
SMAD4 9 and 18 chr9: 127,732,713 chr18: 48,556,624 Manta translocation with breakpoint within untranslated part of exon 1 CNS (42 years) and colorectal (56 years) in mother PMS2, TP53, and MLH1 (single gene) 2011
TSC1 9 135,807,261 135,803,187 Manta duplication of exon 3 testicular (47 years), prostate (64 years), and lung (70 years) BRCA1 and BRCA2 (single-gene Ashkenazi common mutations) 2016
TSC2 16 2,119,769 1,566,500 Manta inversion with breakpoint in introns 16 and 17 small bowel (42 years) and colorectal (43 years) MSH6 (single gene; IHC also revealed MSH6 loss) 2012
FH 1 242,310,908 237,244,834 Canvas full-gene deletion multiple cutaneous leiomyomata (<55 years)a FH (single gene) 2014
The list incorporates one individual per family. All structural variants are heterozygous. The following abbreviations are used: Chr, chromosome; CNS, central nervous system; IHC, immunohistochemistry.
a Tumor characteristically associated with pathogenic variant in the relevant gene.