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S. E. Plon1, L. R. Desrosiers1, S. Scollon2, A. K. Petersen3, H. DAI4, J. Reuther5, G. Miles6, D. M. Muzny4, A. Roy5, S. Kulkarni7, R. A. Gibbs4, A. L. McGuire8, G. E. Tomlinson9, J. Bernini1, J. B. Gill10, T. Griffin11, K. Vallance12; 1Dept. of Pediatrics, Baylor Coll. Med., Houston, TX, 2Baylor Coll. of Med., Houston, TX, 3Randall's Children Hosp. and Legacy Hlth., Portland, OR, 4Baylor Coll. Med., Houston, TX, 5Pathology, Baylor Coll. Med., Houston, TX, 6Molecular and Human Genetics, Baylor Coll. Med., Houston, TX, 7Baylor Genetics, Houston, TX, 8Baylor Col Med, Houston, TX, 9UT Hlth.San Antonio, San Antonio, TX, 10UT MD Anderson Cancer Ctr., Houston, TX, 11Children's Hosp. of San Antonio, San Antonio, TX, 12Cook Children's Med. Ctr., Fort Worth, TX

Background: Multiple studies report that 8-13% of pediatric cancer patients have pathogenic or likely pathogenic variants (PV/LPV) in cancer susceptibility genes, although standards vary for reporting single PV/LPVs in genes associated with autosomal recessive (AR) syndromes. We report here results from two studies of pediatric cancer patients for the frequency of single AR variant results and relationship to the patient’s presentation. Methods: The BASIC3 study included clinical germline and tumor exome sequencing in an ethnically diverse cohort of sequentially diagnosed children with CNS and non-CNS solid tumors. The Texas KidsCanSeq study included germline exome and panel sequencing for pediatric solid tumor patients across six sites in Texas. In both studies, other medical problems noted in the medical record were provided to the reporting laboratory. All result categories on the clinical exome and panel (when available) were returned to parents. Results: Among 278 enrolled patients in BASIC3 there was one patient with two PVs (a homozygous variant in TJP2) and 18 (6.5%) patients had a single PV/LPV in a wide spectrum of AR cancer genes. Only one patient had a tumor type (Wilms tumor) previously associated with the gene (DIS3L2). Patent foramen ovale in a patient with FANCA allele was the only syndromic feature. In the first 366 patients in KidsCanSeq there were no patients with biallelic PV/LPVs, 15 patients (4.1%) with one PV/LPV in AR genes of which 2 had the associated tumor type (DIS3L2 with Wilms tumor and SLC26A4 with thyroid cancer). Not included here are patients with PV/LPV in genes with both AR and dominant cancer phenotypes e.g., ATM. Germline results disclosure with parents discussed (1) their oncologist might request further targeted testing for a 2nd variant if there is concern that the patient has this rare disorder, (2) the patient (and often parent) are carriers of this rare disorder, (3) the lack of evidence relating the variant to the child’s cancer diagnosis and (4) lack of any additional surveillance recommendations.Conclusions: There is increasing use of exome, genome or large hereditary cancer panels for genomic evaluation of cancer patients. Recessive diagnoses are very uncommon but about 5% of pediatric cancer patients have a single PV/LPV in rare AR cancer genes without other findings. These test results require substantial efforts for disclosure and family understanding. We suggest that limiting reporting to biallelic patients or those with features of the disorder including the specific cancer type would streamline the process at the cost of reproductive information. BASIC3 and Texas KidsCanSeq were supported by 1U01HG006485.
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