BACKGROUND:(Likely) pathogenic variants (pVs) in hereditary breast and/or ovarian cancer (HBOC) genes increase cancer risk, but the clinical implications of multiple pVs remain insufficiently understood. METHODS:Using data from the prospective nationwide German Consortium for HBOC registry, we conducted a case-control study of genotype-phenotype associations, matching female carriers to compare cancer risk and disease severity between multiple and single heterozygous (SH) pV carriers. RESULTS:Among 26,983 carriers of single or multiple HBOC-associated pVs, 409 individuals had multiple heterozygosities, including 400 double heterozygous (DH) carriers. In a subcohort tested for 13 core genes, 98/3407 (2.9%) individuals had multiple HBOC-associated pVs. Breast cancers (BCs) in DH women with pVs in BRCA1 and another gene were predominantly triple-negative, even when the second, non-BRCA1 pV was typically associated with hormone receptor (HR)-positive BC. By contrast, BRCA1/CHEK2 DH carriers showed more HR-positive BCs than BRCA1 SH women. The median age at first BC was similar in female ATM/CHEK2 DH carriers and BRCA1 SH carriers (41.5 [IQR 14.0] vs. 41.3 [14.1] years). Matched BRCA1 and BRCA2 SH carriers were less likely to present with higher disease severity than BRCA1/BRCA2 DH carriers (BRCA1: OR 0.396 [0.180-0.87]; BRCA2: OR 0.224 [0.100-0.50]). CONCLUSIONS:Multiple heterozygosity in HBOC core genes is more frequent than previously assumed. Our data indicate that gene-gene constellations can reshape tumour phenotype and clinical severity rather than following single-gene expectations. Integrating multiple pVs into risk assessment and counselling may enhance personalised surveillance and risk-reducing strategies for DH individuals and their families in the era of widespread multigene testing.

Europe’s Beating Cancer Plan is a substantial European Union (EU) investment into cancer prevention and treatment. Integration of genetic services towards personalised cancer prevention and care is a flagship of this plan. Genetic counselling is critical to this integration, facilitating informed patient decision making and improved clinical management. However, growing demands for genetic testing and concurrently increasing workforce shortages necessitate new strategies to equitably ensure sustainable access to counselling across the EU. This project aimed to inform future European activities by identifying priority European strategies for addressing common European genetic literacy, workforce, and reimbursement barriers to genetic counselling in cancer noted in prior work. A Delphi survey was conducted, with genetics, oncology, and patient stakeholders invited from all EU Member States. The response rate was 62% (124 total invitations). Over three phases, 77 participants – 28 geneticists; 14 oncologists; 18 genetic counsellors; 16 patient representatives; 1 otherwise qualified expert – rated 19 strategies according to their Importance, Urgency, and Feasibility and selected their top three priority strategies. Five strategies met pre-defined consensus thresholds and received a clear plurality of priority ratings: (1) EU-wide genetic counsellor recognition; (2) Including genetics expertise in oncology guideline creation; (3) Shared EU genetic counsellor registration/education with legal weight; (4) Mandatory counselling reimbursement when clinical guidelines are met; (5) Mandatory inclusion of genetics in oncology fellowship/continuing education. Results provide a roadmap of European actions which promise to sustainably improve access to genetic counselling in cancer care. Upcoming and ongoing EU projects promise to advance their implementation.

Deleterious germline RUNX1 variants lead to familial platelet disorder with myeloid malignancies (FPDMM), an autosomal dominant disorder characterized by thrombocytopenia, qualitative platelet defects, and an increased risk of hematologic malignancies. Interpretation of variants of uncertain significance (VUSs) remains a major barrier to precision medicine for affected individuals and families, particularly because many RUNX1 variants are private. To address this challenge, we developed a comprehensive pipeline of well-established in vitro functional assays, including transactivation reporter assays, electrophoretic mobility shift assays, western blotting with cell fractionation, and immunofluorescence imaging to assess subcellular localization. We evaluated the functional impact of 26 RUNX1 VUSs identified in individuals referred to the NIH RUNX1 Natural History Study. Five established benign and six pathogenic variants were included as controls. Functional data were integrated with population allele frequencies, in silico predictions, and clinical phenotype and segregation data, enabling reclassification of 17 variants. Our findings also reveal key limitations of the current MM-VCEP variant interpretation guidelines, including overly stringent thresholds that exclude functionally impaired variants from classification. In addition, we demonstrate that the currently approved assays inadequately capture the pathogenic impact of C-terminal variants. These results underscore the importance of comprehensive functional data to support RUNX1 variant classification and inform clinical interpretation. Moreover, this work facilitates investigation of FPDMM pathogenesis and supports refinement of RUNX1-specific variant curation guidelines. We further advocate for development of additional functional assays, especially for variants affecting the RUNX1 C-terminus.

BackgroundRUNX1-familial platelet disorder with associated myeloid malignancy (RUNX1-FPDMM) is caused by heterozygous germline variants of RUNX1. With the broader application of next-generation sequencing (NGS)-based gene panel analysis in individuals presenting with benign hematologic abnormalities such as thrombocytopenia, pathogenic RUNX1 variants were more frequently identified, independent of a hematologic malignancy.ObjectiveThis study aimed to describe the clinical and genetic characteristics of individuals with pathogenic germline RUNX1 variants, with a particular focus on platelet function and diagnostic challenges.MethodsWe retrospectively analyzed 10 individuals from 6 families with genetically confirmed RUNX1-FPDMM. Platelet counts and function were evaluated using light transmission aggregometry (LTA) and flow cytometry (FC). For genetic analysis, NGS-based panel sequencing for inherited platelet disorders, Sanger sequencing, karyotyping, fluorescence in situ hybridization (FISH), and microarray analysis were performed.ResultsPlatelet counts ranged between 40 and 208 G/L. In all six tested individuals, LTA revealed impaired aggregation in response to collagen, adenosine diphosphate (ADP), and epinephrine. FC analysis identified a pronounced granule secretion defect in three of the eight tested individuals. Disease-causing RUNX1 variants included whole-gene or intragenic deletions, one missense, two not previously reported non-sense variants, and a mosaic RUNX1 loss most probably due to the loss of a derivative chromosome 21. One patient has developed acute myeloid leukemia (AML), and another was diagnosed with RUNX1-FPDMM due to thrombocytopenia onset following T-lymphoblastic lymphoma.ConclusionRUNX1-FPDMM is a challenging disease due to its associated increased risk for hematologic malignancies, mainly myelodysplastic syndrome (MDS) or AML. Genetic diagnosis in individuals with thrombocytopenia or functional platelet defects of unknown origin is crucial to offer structured surveillance and patient education. Increased risk of bleeding due to qualitative platelet function defects, particularly granule secretion abnormalities, must be considered when managing patients, especially prior to invasive procedures.

BACKGROUND & AIMS:Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome. The choice of extended or partial colectomy in patients with LS with primary CRC may influence the risk of metachronous CRC. This study aimed to identify factors associated with metachronous CRC risk and evaluate their potential implications for surgical decision-making. METHODS:We analyzed data from the German Consortium for Familial Intestinal Cancer of patients with LS who underwent either extended or partial colectomy for primary CRC. Cox regression models were used to assess the risk of metachronous CRC, adjusting for sex, age, tumor location, surveillance adherence, and gene. RESULTS:Among 852 LS carriers, 21.1% developed metachronous CRC over a median follow-up of 7.9 years. Among high-risk patients with LS, partial colectomy was associated with a borderline nonsignificant increased risk of metachronous CRC of 3.78 (95% confidence interval, 0.93-15.34; P = .063) compared with extended colectomy. Male sex (hazard ratio [HR], 2.16; P < .001), older age at primary CRC diagnosis (HR, 1.03; P < .001), and left-sided tumor location (HR, 1.53; P = .037) were additional risk factors. Surveillance adherence was not significantly associated with metachronous CRC risk. CONCLUSIONS:This study identifies important risk factors for metachronous CRC in patients with LS, which may support personalized counseling regarding surgical strategies. The findings highlight the complexity of surgical decision-making and the need for individualized approaches. Further studies are required to refine risk stratification and evaluate long-term outcomes to optimize patient care.

One in 12 malignancies is diagnosed in a young adult between 20 and 39 years of age. One of the most relevant known causes of cancer in this age group, which is present in approximately 10% of cancer patients, is genetic cancer predisposition that originates from constitutional or postzygotic somatic (epi-)genetic variants leading to an increased cancer risk compared with the general population. The diagnosis of a cancer predisposition syndrome is important because it can affect cancer surveillance, prevention, and therapy. Universal gene-panel germline sequencing is offered by some centers; however, in clinical settings with limited resources, cancer predisposition syndrome screening tools can support the identification of those cancer patients who may benefit from genetic counseling and/or testing regarding underlying genetic diseases. Effective screening tools have been developed for children with cancer, but comparable cancer predisposition syndrome screening algorithms are lacking for young adults with cancer. We present here an easy-to-use cancer predisposition syndrome screening tool designed specifically for young adults with cancer. By combining available recommendations and disease-specific criteria, the algorithm is focusing on somatic genetic findings in malignant cells, specific cancer types strongly associated with cancer predisposition syndromes, and the personal and family past medical history. This tool may increase clinical awareness among oncologists and facilitate the diagnoses of cancer predisposition syndromes in young adults with cancer.

Paediatric blast-phase chronic myeloid leukaemia (CML-BP) is a rare and serious condition. Of 231 paediatric patients enrolled in the German CML-PAED-II registry between January 2007 and September 2023, 25 individuals (11%) were diagnosed with CML-BP. To identify genetic variants associated with early onset and disease transformation, we performed whole genome sequencing (WGS), deep targeted sequencing and cytogenetic analyses in 19 cases with de novo (n = 11) or secondary (n = 8) CML-BP and sufficient available biomaterial. Copy number variants (CNVs) were more frequent than single nucleotide variants (SNVs) and more prevalent in secondary than in de novo CML-BP. Recurrent pathogenic somatic SNVs were observed in ABL1 (n = 5, 24%), RUNX1 (n = 2, 12%) and ASXL1 (n = 2, 12%). Nine patients (47%) carried pathogenic germline (n = 8) or somatic (n = 1) variants in either of the genes ATM, CHEK2, FANCM, HERC2, NBN, RAD54B, RECQL4, SETD2 or TP63 belonging to the DNA damage response (DDR). Within a comparison cohort of 19 patients with chronic phase paediatric CML, only one individual (5%) exhibited a pathogenic DDR germline variant. Our study provides novel pathogenetic insights into paediatric CML-BP. The identification of pathogenic DDR-associated germline variants suggests a genetic predisposition with potential implications for patients and families concerning cancer treatment and surveillance.

Li-Fraumeni syndrome is a cancer predisposition syndrome caused by pathogenic TP53 germline variants; it is associated with a high lifelong cancer risk. We analyzed the German Li-Fraumeni syndrome registry, which contains data on 304 individuals. Cancer phenotypes were correlated with variants grouped according to their ability to transactivate target genes in a yeast assay using a traditional (nonfunctional, partially functional) and a novel (clusters A, B, and C) classification of variants into different groups. Partially functional and cluster B or C variants were enriched in patients who did not meet clinical testing criteria. Time to first malignancy was longer in carriers of partially functional variants (hazard ratio = 0.38, 95% CI = 0.22 to 0.66). Variants grouped within cluster B (hazard ratio = 0.45, 95% CI = 0.28 to 0.71) or C (hazard ratio = 0.34, 95% CI = 0.19 to 0.62) were associated with later cancer onset than NULL variants. These findings can be used to risk-stratify patients and inform care.

Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM, FPD/AML, RUNX1-FPD), caused by monoallelic deleterious germline RUNX1 variants, is characterized by bleeding diathesis and predisposition for hematologic malignancies, particularly myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Clinical data on FPDMM-associated AML (FPDMM-AML) are limited, complicating evidence-based clinical decision-making. Here, we present retrospective genetic and clinical data of the largest cohort of FPDMM patients reported to date. We describe 159 European patients (from 94 families) of whom 134 were evaluable for the development of malignant disease. Sixty developed a hematologic malignancy (44.8%), most frequently AML (36/134, 26.9%) or MDS (18/134, 13.4%). Somatic alterations of RUNX1 by gene mutation (48%) and chromosome 21 aberrations (14.3%) were the most common somatic genetic aberrations in FPDMM-AML, followed by FLT3-ITD mutations (24.1%). Somatic RUNX1 and FLT3-ITD mutations were not detected in FPDMM-associated MDS, suggesting important contributions to leukemic transformation. Remission-induction chemotherapy resulted in complete remission in 80% of FPDMM-AML patients with a 5-year overall survival (OS) of 50.4%. Survival outcome was non-inferior compared to a large cohort of newly diagnosed adult RUNX1-mutated AML (5-year OS 36.6%, p = 0.5), with relatively infrequent concurrent adverse risk somatic aberrations (ASXL1 mutation, monosomal karyotype, monosomy 5/del 5q) in FPDMM-AML. Collectively, data support the notion that step-wise leukemic evolution in FPDMM is associated with distinct genetic events and indicate that a substantial subset of FPDMM-AML patients achieves prolonged survival with conventional AML treatment, including allogeneic stem cell transplant. These findings are anticipated to inform personalized clinical decision-making in this rare disorder.

Large genomic rearrangements (LGRs) within the human genome are becoming more recognized by novel genome-wide technologies and may be underreported so far. This class of genomic variation includes copy number variations like duplications or triplications of coding or non-coding genomic regions. Here, we report two LGRs targeting BRCA1, a duplication of exons 18-19 and a triplication of exons 1-2 in two independent families. Utilizing Optical Genome Mapping (OGM), Whole Genome Sequencing (WGS) and cDNA analysis, we characterized the genomic organization and transcriptomic effects of these LGRs regarding its. We show that the tandem duplication ogm[GRCh38]dup(17)(q21.31q21.31)(43057052_43063373), targeting BRCA1 exon 18-19 is predicted to generate a premature termination codon, namely p.(His1732Metfs*10). The triplication of BRCA1 exon 1-2 ogm[GRCh38]trip(17)(q21.31q21.31)(43117155_43124115) is also sequentially arranged. The transcript shows an insertion of a small part of intron 2 (chr17:43,121,558-43,121,676) that theoretically will generate a premature termination codon as well. Collectively, OGM and WGS help elucidating the architecture of these LGRs. However, the final curation depends on how adequate the functional consequences of these LGR can be clarified. Deeper investigation of LGRs on transcript level is important to attain accurate conclusions with respect to therapeutic decisions.

Germline (likely-)pathogenic variants (PV) in CDH1 predispose carriers to hereditary diffuse gastric cancer and lobular breast cancer. Previous studies from the United States suggest CDH1 variant carriers have an increased risk for adenomas or sessile serrated lesions (SSL), yet data linking CDH1 PVs and colorectal neoplasia are scarce. We aimed to investigate colonoscopy findings in CDH1 PVs. Adults carrying a PV/LPV in CDH1 with ≥ 1 colonoscopy between 01/01/2004–12/31/2023 were included. Patients were sourced from the David G. Jagelman Inherited Colorectal Cancer Registries at Cleveland Clinic and the German Consortium for Familial Intestinal Cancer. 103 CDH1 PV carriers were included. Most were female (66

Genetic cancer predisposition is an important cause of cancer across all age groups. Approximately ten percent of cancer patients have an underlying cancer predisposition syndrome (CPS) and we estimate that 500,000 individuals with a CPS live in Germany. Gene panel germline or tumour-germline genetic testing is increasingly employed in cancer patients resulting in rising numbers of CPS diagnoses. Such a diagnosis is only useful if affected individuals are appropriately counselled and if recommended clinical consequences in the areas of cancer prevention, surveillance, and therapy can be implemented. While care pathways for individuals with hereditary breast and ovarian cancer and familial colon cancer syndromes exist, sufficient interdisciplinary care structures for individuals with rare CPSs are currently lacking. The aim of this viewpoint is to point out that the clinical care pathways for individuals with rare CPSs need to be improved. We describe a model CPS clinic that systematically collects data to allow future evidence-based adaptation of care and propose the establishment of a collaborating network of similar clinics in Germany. This message is directed to individuals with a CPS, health care providers, insurance companies, and politicians in Germany and may be relevant for other health care systems as well.

Background Somatic and germline genetic alterations are significant drivers of cancer. Increasing integration of new technologies which profile these alterations requires timely, equitable and high-quality genetic counselling to facilitate accurate diagnoses and informed decision-making by patients and their families in preventive and clinical settings. This article aims to provide an overview of genetic counselling legislation and practice across European Union (EU) Member States to serve as a foundation for future European recommendations and action.Methods National legislative databases of all 27 Member States were searched using terms relevant to genetic counselling, translated as appropriate. Interviews with relevant experts from each Member State were conducted to validate legislative search results and provide detailed insights into genetic counselling practice in each country.Results Genetic counselling is included in national legislative documents of 22 of 27 Member States, with substantial variation in legal mechanisms and prescribed details (i.e. the 'who, what, when and where' of counselling). Practice is similarly varied. Workforce capacity (25 of 27 Member States) and genetic literacy (all Member States) were common reported barriers. Recognition and/or better integration of genetic counsellors and updated legislation and were most commonly noted as the 'most important change' which would improve practice.Conclusions This review highlights substantial variability in genetic counselling across EU Member States, as well as common barriers notwithstanding this variation. Future recommendations and action should focus on addressing literacy and capacity challenges through legislative, regulatory and/or strategic approaches at EU, national, regional and/or local levels.