Low-frequency CDKN1B variants in pituitary testing: a diagnostic pitfall

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Abstract
Low-variant allele frequency (VAF) variants identified during germline testing may represent constitutional mosaicism or acquired somatic events restricted to hematopoietic cells. Although clonal hematopoiesis of indeterminate potential (CHIP) has emerged as an important source of interpretative pitfalls in hereditary cancer testing, its potential impact on the interpretation of CDKN1B variants has not been specifically emphasized. We aimed to determine whether low-VAF CDKN1B variants detected during routine germline testing for pituitary adenoma predisposition may represent clonal hematopoiesis rather than true constitutional alterations. We analyzed patients referred for routine genetic investigation of pituitary adenoma predisposition who has low-frequency CDKN1B variants identified in blood-derived DNA. Additional analyses were performed, including assessment of variant distribution in nonhematopoietic tissues, tumor DNA analysis, and investigation of CHIP-associated genes. Three unrelated patients carrying truncating CDKN1B variants were identified, with blood-derived VAFs ranging from 4% to 6%. Clinical presentations included 2 gonadotroph macroadenomas diagnosed later than age 70 years and 1 prolactin-secreting macroadenoma diagnosed before age 35. CDKN1B variants were absent in buccal swab DNA and from available pituitary tumor DNA. Additional pathogenic variants affecting CHIP-associated genes were identified in 2 individuals. Collectively, these findings supported a leukocyte-restricted origin of the CDKN1B variants and suggested CHIP as the most likely explanation. Low-frequency CDKN1B variants detected during blood-based germline testing should not automatically be interpreted as constitutional mosaicism or inherited endocrine tumor predisposition. Integration of tissue-specific analyses and consideration of CHIP-related findings are essential to avoid inappropriate genetic counseling, unnecessary familial investigations, and misleading surveillance recommendations.

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