LAUSR

Fumarate Hydratase (FH) mutations underpin the autosomal recessive syndrome Fumarate Hydratase deficiency and the autosomal dominant syndrome Hereditary Leiomyomatous and Renal Cell Carcinoma (HLRCC). The variant rs367543046, a duplication leading to p. Lys477_Asn478insLys in FH has strong evidence for risk towards fumarate hydratase deficiency when occurring in trans to another germline alteration in the FH gene. In addition, this variant in the heterozygous state has been reported in ClinVar to predispose to the autosomal dominant condition HLRCC, given other heterozygous mutations have shown to be pathogenic. Population level data is sparse to determine the variant’s impact in the heterozygous state. Here, we show in a series of 1375 cancer cases the (rs367543046, chr1: 241661227 A/ATTT), variant detected in 7 (0.5%) individuals with cancer. One patient with bladder cancer had a history of uterine leiomyomas, but the immunohistochemistry for 2SC was negative, suggesting that the leiomyomas were not associated with HLRCC. None of the other 6 carriers of this variant had any features of HLRCC. Notably, this variant was not detected in any of the patients with renal cancer (n=178) participating in the study. Since 4/7 prostrate cancer patients of Ashkenazi ethnicity harbored this variant, we performed a genetic epidemiology study using 856 Ashkenazi Jewish prostate cancer patients. The allele frequencies were compared with 557 Ashkenazi Jewish non-cancer controls. A fisher’s two sided exact test showed that the variant is not associated with prostate cancer in Jews (P=1, OR 1.12(CI 95% 0.21-7.25). Our findings suggest that the variant, which is pathogenic for autosomal recessive fumarate hydratase deficiency does not confer pathogenicity in the heterozygous form for Hereditary Leiomyomatous and Renal Cell Carcinoma or prostate cancer. Citation Format: Michael F. Walsh, Diana Mandelker, Joseph Vijai, David Musheyev, Jennifer Kennedy, Zsofia Stadler, Yelena Kemel, Sabine Topka, Karen Cadoo, Maria Carlo, Marc Ladanyi, Mark Robson, Kenneth Offit, Liying Zhang. FH (rs367543046, chr1:241661227 A/ATTT) heterozygous carrier status does not confer risk to hereditary leiomyomatosis and renal cell cancer (HLRCC) and prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4280. doi:10.1158/1538-7445.AM2017-4280