PMC:6037202 / 45759-47216 JSONTXT

{"project":"2_test","denotations":[{"id":"29909963-26556299-2051633","span":{"begin":420,"end":422},"obj":"26556299"},{"id":"29909963-27978560-2051634","span":{"begin":428,"end":430},"obj":"27978560"},{"id":"29909963-15492928-2051635","span":{"begin":1061,"end":1063},"obj":"15492928"},{"id":"29909963-24949998-2051636","span":{"begin":1323,"end":1325},"obj":"24949998"},{"id":"29909963-24429628-2051637","span":{"begin":1452,"end":1453},"obj":"24429628"},{"id":"29909963-1961222-2051638","span":{"begin":1455,"end":1457},"obj":"1961222"}],"text":"In this study, we applied multi-gene testing in all affected individuals irrespective of the tumor types diagnosed. Strikingly, this resulted in the identification of a large number of probands (29/67 [43.2%]) who harbored a P/LP CPG variant but whose tumor phenotypes were not entirely typical for the relevant CPG. This situation has been frequently reported by other studies of extensive NGS testing of cancer cohorts37, 40, 42 and represents a challenge for clinicians because the relevance of the variant to cancer risk in the consultand (including unaffected family members) is less clear. Specific atypical associations observed in this analysis were heterogeneous, and numbers were small, but some patterns were noted; for example, 5/16 (31.2%) carriers of CHEK2 variants had been previously diagnosed with renal cell carcinoma (RCC) (breast cancer occurred in 8/16 [50%]). An odds ratio of 2.1 for RCC has previously been observed in CHEK2-variant carriers but only in association with the c.470T\u003eC (p.Ile157Thr) founder variant in a Polish population.43 2/6 (33.3%) carriers of PALB2 variants had cutaneous melanoma before the age of 40 years, and 2/10 (20%) individuals with ATM variants had thyroid cancer before that age, but an analysis of 182 melanoma families demonstrated only one pathogenic PALB2 variant,44 and thyroid malignancies have not been reported at increased frequency in carriers of homozygous or heterozygous ATM variants.1, 45"}