Identification of germline mutation
We performed whole-exome sequencing of the proband’s tumor and
peripheral blood. Splice site mutation in FH(c.378+1G>A; NM_000143) was detected on both tumor
[variant allele frequency (VAF): 73.2%] and peripheral blood (VAF:
46.5%), and validated by Sanger sequencing (Fig.1F ). The
higher VAF in tumor cells suggests that somatic loss of heterozygosity
(LOH) occurs in tumor cells in addition to germline FH gene
mutation. Sanger sequencing was performed on his parents’ peripheral
blood, and the same heterozygous mutation was identified in his father,
but not his mother (Fig.1F ). His father had a medical history
of prostate cancer, but no renal disease or cutaneous leiomyomas.