Genetic counselling for hereditary cancer predisposition has evolved substantially over more than three decades, driven by advances in genomic technologies and the growing use of tumour and germline testing. These developments have expanded access to hereditary cancer testing, treatment and prevention, while also introducing new clinical, psychosocial and system-level challenges. This review examines the transition from tradit...

Rare pathogenic variants affecting components of the evolutionary conserved cAMP/protein kinase A (PKA) signalling pathway are implicated in a spectrum of adrenocortical disorders. Germline inactivating PRKAR1A variants leading to constitutive PKA activation, underlie primary pigmented nodular adrenocortical disease (PPNAD) in Carney complex. More recently, several patients with PPNAD and other types of bilateral nodular adren...

Genetic testing in ovarian carcinoma (OC) patients is very important for patients and their relatives. The Tumor-First workflow uses a tumor DNA test to stratify germline testing for hereditary cancer predisposition as well as treatment options with PARP inhibitors. This workflow is adopted and successfully implemented nationwide. Here, we evaluated recent tumor DNA testing rates in the Netherlands to identify untested OC pati...

Colorectal cancer (CRC) development in Lynch syndrome (LS) has long been regarded to follow an adenoma-carcinoma sequence accelerated in comparison to microsatellite-stable (MSS) CRC development. Yet, several clinical observations challenged this hypothesis, most notably the persistently high CRC incidence under colonoscopy surveillance, a non-measurable benefit from shorter screening intervals, and substantial differences in...

Pleural mesothelioma (PM) is a malignancy with a relevant genetic component, with germline mutations identified in up to 12% of cases. International guidelines recommend universal germline testing; however, its implementation in routine clinical practice remains inconsistent. This nationwide survey aimed to assess current clinical practice, attitudes, and barriers related to genetic testing among Italian specialists within the...

Background Germline TP53 pathogenic variants are classically associated with Li-Fraumeni syndrome, although penetrance and tumor spectrum vary substantially across specific alleles. The Ashkenazi Jewish TP53 c.1000G > C (p.Gly334Arg) variant has been reported as a lower-penetrance, later-onset cancer predisposition allele, but its clinical classification and penetrance remain subjects of ongoing discussion. Consequently, the o...

Germline pathogenic variants (PVs) in POT1 , one of the shelterin complex genes, correlate with tumor predisposition, primarily with melanoma, hematologic malignancies, sarcoma, papillary thyroid carcinoma and glioma. Breast cancer (BC) risk has not been shown to be elevated. We analyzed BC occurrence and features in a cohort of 29 female PV heterozygotes, of whom 13/29 (45%) were diagnosed with BC. Data regarding genetic, cli...

Lynch syndrome, the most common hereditary cancer syndrome, is caused by germline pathogenic variants in DNA mismatch repair (MMR) genes. Identifying complex or structural MMR gene pathogenic variants can be challenging with short-read sequencing resulting in patients with unexplained MMR-deficient tumours. In this study, we report multiple members of a family who developed MSH2-deficient tumours where clinical multi-gene pane...

CDH1 pathogenic variant carriers are at high lifetime risk of hereditary diffuse gastric cancer (HDGC). Endoscopic surveillance is recommended for individuals who delay risk-reducing total gastrectomy, although detection of signet ring cell carcinoma (SRCC) remains challenging. No Australian cohort has reported real-world endoscopic performance with surgical correlation in this population. We performed a 15-year retrospective...

Peutz-Jeghers Syndrome (PJS) is caused by germline pathogenic variants in the STK11 gene and is associated with elevated lifetime risks for several cancers, including lung cancer. Currently, no formal recommendations exist for lung cancer screening in PJS. This structured narrative review compares lung cancer risk in PJS with lung cancer risk in individuals currently eligible for screening based on age and smoking history. Pub...

Constitutional mismatch repair deficiency (CMMRD) is a rare and likely the most penetrant cancer predisposition syndrome caused by biallelic germline variants in a mismatch repair gene. Patients typically develop a spectrum of malignancies, including brain tumors, gastrointestinal cancers, and hematological neoplasms within the first two decades of life. Since its initial description in 1999, two international consortia, the I...

NF2 -Related Schwannomatosis ( NF2 -SWN) is a rare tumor predisposition syndrome characterized by heterogeneous clinical manifestations that substantially impact quality of life (QOL). In this diverse patient population, a disease-specific QOL instrument is essential for both research and clinical decision-making. Insight into factors associated with QOL may further facilitate the tailoring of management strategies to individu...

Von Hippel-Lindau (VHL) disease is a hereditary tumor predisposition syndrome caused by pathogenic germline variants in the VHL gene. Patients with VHL disease have an increased risk of developing characteristic VHL disease-associated lesions such as clear cell renal cell carcinoma, retinal angioma, central nervous system hemangioblastoma, pancreatic neuroendocrine tumors and pheochromocytomas. Loss of the VHL gene results in...