RESUMEN
OBJECTIVE: To examine the effect of patient-selected opt-in versus opt-out option on the rate of reported variants of uncertain clinical significance (VOUS) and high-frequency low-penetrant (HFLP) findings in prenatal microarray testing. METHODS: A standard microarray consent form in Israel includes a requirement to note patient choice to be or not to be informed about the presence of VOUS and HFLP variants. The original form was designed as an opting-out method, in which the women had to actively mark if they did not want to be informed about questionable findings. In the authors' Genetic Institute, the form was changed for an opting-in option in October 2019. In this study we have compared the rates of reported VOUS and HFLP variants between the opt-in and opt-out periods. RESULTS: Of the 1014 prenatal CMA tests, 590 (58.2%) were performed in the opt-out period. A significant decrease in the rate of women requesting to be informed of VOUS findings was noted (66.8% in opt-out period vs 34.0% in opt-in period), yielding a relative risk (RR) of 0.46 (95% confidence interval [CI] 0.39-0.53). Rate of women preferring to be informed of HFLP variants decreased from 75.3% to 48.1% (RR 0.52, 95% CI 0.45-0.60). DISCUSSION: We present a simple and effective method to decrease the rate of reported findings of questionable significance in the prenatal setting. These results are important not only for microarray results, but also for next-generation sequencing techniques, such as whole exome or genome sequencing.
RESUMEN
POT1 (Protection of Telomeres 1) is a key component of the six-membered shelterin complex that plays a critical role in telomere protection and length regulation. Germline variants in the POT1 gene have been implicated in predisposition to cancer, primarily to melanoma and chronic lymphocytic leukemia (CLL). We report the identification of POT1 p.(I78T), previously ranked with conflicting interpretations of pathogenicity, as a founder pathogenic variant among Ashkenazi Jews (AJs) and describe its unique clinical landscape. A directed database search was conducted for individuals referred for genetic counselling from 2018 to 2023. Demographic, clinical, genetic, and pathological data were collected and analyzed. Eleven carriers, 25 to 67 years old, from ten apparently unrelated families were identified. Carriers had a total of 30 primary malignancies (range 1-6); nine carriers (82%) had recurrent melanoma between the ages of 25 and 63 years, three carriers (27%) had desmoid tumors, three (27%) had papillary thyroid cancer (PTC), and five women (63% of female carriers) had breast cancer between the ages of 44 and 67 years. Additional tumors included CLL; sarcomas; endocrine tumors; prostate, urinary, and colorectal cancers; and colonic polyps. A review of a local exome database yielded an allelic frequency of the variant of 0.06% among all ethnicities and of 0.25% in AJs. A shared haplotype was found in all carriers tested. POT1 p.(I78T) is a founder disease-causing variant associated with early-onset melanoma and additional various solid malignancies with a high tumor burden. We advocate testing for this variant in high-risk patients of AJ descent. The inclusion of POT1 in germline panels for various types of cancer is warranted.