Submission Details

STK11 was first reported in relation to autosomal dominant Peutz-Jeghers syndrome (PJS) in 1998 (Jenne et al. and Hemmiki et al., PMIDs 9425897 and 9428765). PJS is characterized by the development of gastrointestinal (GI) PJS-type hamartomatous polyps and mucocutaneous hyperpigmentation, which most often presents in childhood and fades by puberty. GI polyps present a significant clinical burden and can cause chronic bleeding and intussusception in individuals with PJS. Individuals with PJS have been reported to have an increased cumulative lifetime risk for various cancers, including female breast cancer, colorectal cancer, stomach cancer, small bowel cancer, pancreatic cancer, lung cancer, endometrial cancer, cervical cancer, non-epithelial sex cord tumors of the ovary, and Sertoli cell testicular tumors. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern and phenotypic variability. Therefore, the described phenotypic manifestations and tumor spectrum has been lumped into one disease entity: Peutz-Jeghers syndrome (OMIM: 175200). Fourteen variants (missense, in-frame deletions/insertions, nonsense, frameshift, large deletion, complex rearrangements) that have been reported in 14 probands in 5 publications (PMIDs: 9425897, 9428765, 12865922, 15121768, 30689838) were included in this curation. Variants reported are largely truncations and gross deletions, and additional evidence of familial co-segregation supports their association with PJS. Furthermore, large-scale meta analyses and case control analyses show the association of cancer susceptibility in individuals with PJS (PMIDs: 23415580, 11113065, 16707622). Data from these studies is largely from highly-ascertained cohorts and may overestimate cancer risks. At least one large-scale population-based study contradicts the high risk of breast cancer reported in the literature (PMID: 33471991). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss-of-function. This gene-disease association is also supported by experimental evidence (6 points, PMIDs: 15800014, 10441497, 15261145, 19681070, 12226664, 15987703, 9425897). In non-patient cells (mouse embryonic fibroblasts), deleterious effects such as hyperactivated mTOR signaling was observed when Stk11 was lost. Mouse models of loss of Stk11 replicating the human phenotype including mammary tumors and small intestine hamartomatous polyps. In summary, STK11 is definitively associated with autosomal dominant Peutz-Jeghers syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated as definitive on 2/22/2017 by Colon Cancer GCEP. This re-curation was approved by the ClinGen Hereditary Cancer GCEP on 5/26/2023 (SOP Version 9).