Reclassification of an uncertain STK11 germline variant as likely pathogenic: a family study

Early-onset breast cancer in a woman prompted referral for genetic counseling, due to suspected hereditary cancer predisposition. After collecting a detailed personal and family medical history and providing comprehensive pre-test counseling, the patient consented to a multigene panel test for breast cancer susceptibility. Genetic analysis revealed a germline variant, c.662 C > T p.(Pro221Leu), in the STK11 gene, initially classified as a variant of unknown significance (VUS). Given the possibility of Peutz-Jeghers syndrome (PJS), a thorough review of the patient's extended family history was undertaken to identify clinical features consistent with the syndrome. The maternal grandmother's lineage revealed a striking aggregation of malignancies, including eight cases of breast cancer (ages 34-73), one suspected gastric cancer before age 50, and five individuals with colorectal polyps. On the maternal grandfather's side, nine breast cancer cases (ages 34-77), one childhood skin cancer, and one endometrial cancer at age 56 were described. Segregation studies in multiple relatives demonstrated co-segregation of the STK11 variant with disease. This evidence supported the reclassification of the STK11 c.622 C > T p.(Pro221Leu) variant as likely pathogenic. Consequently, carriers were enrolled in syndrome-specific surveillance protocols for PJS. This case underscores the essential role of comprehensive clinical and familial assessment, alongside segregation studies, in refining variant interpretation and enabling personalized, syndrome-specific management strategies.