TP53 pathogenic variants cause Li-Fraumeni syndrome (LFS), with some variants causing an attenuated phenotype. Herein, we describe the clinical phenotype and genetic characteristics of carriers of NM_000546.6 (TP53): c.541C > T, (p.Arg181Cys) treated at Hadassah Medical Center. We retrospectively examined our genetic databases to identify all carriers of TP53 p.Arg181Cys. We reached out to carriers and their relatives and collected clinical and demographic data, lifestyle factors, carcinogenic exposures as well as additional blood samples for genetic testing and whole exome sequencing. Between 2005 and 2022 a total of 2875 cancer patients underwent genetic testing using genetic panels, whole exome sequencing or targeted TP53 assays. A total of 30 cancer patients, all of Arab-Muslim descent, were found to be carriers of TP53 p.Arg181Cys, the majority from Jerusalem and Hebron, two of which were homozygous for the variant. Carriers were from 24 distinct families of them, 15 families (62.5%) met updated Chompret criteria for LFS. Median age of diagnosis was 35 years-old (range 1–69) with cancers characteristic of LFS (16 Breast cancer; 6 primary CNS tumors; 3 sarcomas) including 4 children with choroid plexus carcinoma, medulloblastoma, or glioblastoma. A total of 21 healthy carriers of TP53 p.Arg181Cys were identified at a median age of 39 years-old (range 2–54)—19 relatives and 2 additional pediatric non-cancer patients, in which the finding was incidental. We report a shared haplotype of 350kb among carriers, limited co-morbidities and low BMI in both cancer patients and healthy carriers. There were no demographic factors or carcinogenic exposures unique to carriers who developed malignancy. Upon exome analysis no other known pathogenic variants in cancer predisposing genes were identified. TP53 p.Arg181Cys is a founder pathogenic variant predominant to the Arab-Muslim population in Jerusalem and Hebron, causing attenuated-LFS. We suggest strict surveillance in established carriers and encourage referral to genetic testing for all cancer patients of Arab-Muslim descent in this region with LFS-associated malignancies as well as family members of established carriers.

BAP1 germline pathogenic sequence variants (PSVs) underlie a unique tumor predisposition syndrome (BAP1 ‐ TPDS) associated with increased lifetime risk for developing primarily pleural and peritoneal mesothelioma and uveal and cutaneous melanoma. Overwhelmingly, BAP1 PSVs are unique, family specific inactivating variants. We identified seven families, 6 of Jewish Iraqi origin, harboring an identical BAP1 splice variant (c.783+2T>C), currently assigned a “likely pathogenic” status. Given a non‐classical BAP1‐TPDS tumor type clustering, and low penetrance in these families, the pathogenicity of this variant was re‐evaluated by a combined approach including literature analysis, revised bioinformatics analysis, allelic loss, effect on transcript, and tumor protein expression patterns. None of three available tumors showed allelic loss, there was no discernable effect on alternative splicing based on reverse transcription PCR, and there was no decrease or loss of somatic protein expression in 2/3 analyzed tumors. This led to assigning a Benign Strong (BS) criteria, BS4, supporting BS3 criteria, and to weakening the Pathogenic Supporting (PP) criteria PP5. Combined, these data suggest that this sequence variant should be re‐classified as a variant of unknown significance by ACMG criteria.

Founder pathogenic variants (PVs) are prevalent in Israel. This study investigated the current practice of offering cancer patients two-step genetic testing, starting with targeted testing for recurring founder PVs, followed, if negative, by next-generation sequencing. A total of 2128 subjects with cancer or a positive family history underwent oncogenetic testing with a panel of 51 recurring PVs at a tertiary medical center in March 2020–January 2023. Those with a known familial PV (n = 370) were excluded from the analysis. Among the remainder, 128/1758 (7%) were heterozygous for at least one variant, and 44 (34%) carried a PV of medium-high penetrance (MHPV). Cancer was diagnosed in 1519/1758 patients (86%). The diagnostic yield of founder MHPV testing was 2% in cancer patients and 4% in healthy individuals with a positive family history. It was higher in Ashkenazi Jews than non-Ashkenazi Jews and Arabs, but not over 10% for any type of cancer, and it was significantly higher in younger (50 years) individuals (7% vs. 1%). Eighty-four of the heterozygotes (66%), mostly Ashkenazi Jews, harbored a low-penetrance variant (LPV) not associated with the diagnosed cancer, usually APC c.3902T>A. These findings question the advantage of two-step testing. LPVs should not be included in targeted testing because this can lead to an overestimation of the yield, and their detection does not preclude further comprehensive testing.

Background: Genomic sequencing yields vast amounts of data, and the access of patients and research participants to their raw genomic data raises ethical and practical dilemmas. Purpose: This paper aims to examine a challenging, underexplored question: whether gamete donors' raw data should be provided to recipient parents. Methods: Using a clinical case, we explore the key ethical, legal, and clinical implications of such access, weighing the advantages, disadvantages, and potential alternatives. Results: Ethical implications include the feasibility of meaningful informed consent from donors for complex genetic testing, sometimes years after donation; privacy considerations; the type of medical information recipients can or should hold on donors; potential conflicts of interest between the donor and the child; and the potential for raised costs and commercial interests. Clinical implications involve the implementation of systems of storing donors' raw data and devices of re-contacting past donors. Legal aspects include the informed consent of gametes donors to disclose their raw data to recipient parents and privacy protections, including their right to keep their raw data in confidence. Conclusion: We advocate a cautious approach that favors clinically mediated access over unrestricted parental access.