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Results for “Germ-Line Mutation”

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PubMed2025

Germline variants in CDKN2A wild-type melanoma prone families.

Germline pathogenic variants in CDKN2A are well established as an underlying cause of familial malignant melanoma. While pathogenic variants in other genes have also been linked to melanoma, most familial cases remain unexplained. We assessed pathogenic germline variants in 360 cancer-related genes in 56 Norwegian melanoma-prone families. The index cases were selected based on familial history of melanoma and/or multiple primary melanomas, along with previous negative tests for pathogenic CDKN2A variants. We found 6 out of 56 index individuals to carry germline pathogenic or likely pathogenic variants in BRCA2, MRE11, ATM, MSH2, CHEK2, and AR. One family member with melanoma (not index case) carried a pathogenic variant in MAP3K6. In addition, we found a high fraction of variants previously considered benign and/or as variants of uncertain significance in xeroderma pigmentosum-related genes. In particular, XPCL48F was found in 8 indexes; thus, the allele fraction (0.07) was significantly higher than in comparable healthy populations (0.02-0.03; P-values from 0.007 to 0.014). In conclusion, we found that several melanoma-prone families have pathogenic variants in genes not usually linked to melanoma.

Humans↗

PubMed2026

Uptake of germline testing for Lynch Syndrome in patients with deficient mismatch repair/ microsatellite-high colorectal cancer in the public hospital system in South Australia.

Lynch syndrome (LS) accounts for approximately 4% of colorectal cancer (CRC) cases and arises from pathogenic variants in mismatch repair (MMR) genes. Australian guidelines recommend universal MMR or microsatellite instability (MSI) screening in all CRC patients; however, real-world uptake remains variable. This study evaluated rates of MMR/MSI screening, germline testing, and genetics referrals across two major public hospitals in South Australia. A retrospective review of 1775 patients discussed at colorectal multidisciplinary team meetings in the Royal Adelaide and Queen Elizabeth hospitals between January 2021 and December 2023 was conducted to identify rates of MMR/MSI screening and subsequent referral of eligible patients to genetics. Of the 1129 colorectal cancer cases identified, MMR/MSI testing was performed in 93.2% (1052/1129), with deficiency detected in 12.5% (131/1052). Of these, 37% (49/131) were eligible for genetics referral after exclusion of somatic causes. Among eligible patients, 73.5% (36/49) were referred, and 43% (21/49) underwent germline testing. LS was confirmed in 12 patients (9% of deficient MMR CRC), while 9 patients (6.9%) were classified as having Lynch-like syndrome. Despite high screening rates, gaps remain in genetics referral and testing. Barriers included lack of reflex testing, loss to follow-up, and patient refusal. Targeted system-level interventions and improved genomic education are needed to enhance adherence to guidelines and optimise patient outcomes.

Humans↗

PubMed2026

Shared inheritance reveals landscape of somatic and germline cancer risk in TP53.

Pathogenic variants in TP53, the key tumor suppressor gene underlying Li-Fraumeni syndrome (LFS), are among the best-established causes of inherited cancer predisposition. However, large-scale sequencing has revealed that many apparently pathogenic TP53 variants detected in blood are the result of somatic clonal expansions, complicating risk interpretation. Using blood-derived whole-exome data from 469,391 UK Biobank participants, we combined the variant allele fraction (VAF) with haplotype-sharing analysis to distinguish germline and somatic TP53 variants. Germline variants were concentrated at sites linked to partial loss of p53 function and lower disease penetrance, whereas classic LFS alleles appeared to be predominantly somatically acquired. Classic LFS alleles at high VAF conferred markedly increased risk of hematological malignancy but not solid tumors, indicating an important contribution from large TP53-mutant clonal expansions. The prevalence of somatic clonal expansion also correlated with missense variant pathogenicity, suggesting that somatic activity provides an informative in vivo proxy for functional impact. These results provide new insights into TP53-associated cancer risk at the population level, demonstrate that somatic rather than germline risk predominates in middle-aged healthy adults, and provide a scalable framework for variant classification in large-scale population genomics.

Humans↗

PubMed2026

RNA splicing evidence enables robust classification of BRCA1 exon 18 variants: Results from the ENIGMA consortium.

The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) research consortium conducted a comprehensive study to characterize spliceogenic variants in BRCA1 exon 18. The absence of systematic RNA-based assessment for these variants has led to inconsistent interpretation, limiting accurate classification and management of individuals and their families. The splicing profile of 166 variants was assessed using minigene assays; 32 were additionally analyzed in blood-derived RNA from 51 individuals and 18 in mouse embryonic stem cell (mESC)-based assays to evaluate homology-directed repair (HDR) capacity. mRNA assessment by RT-PCR in blood samples and minigene assays showed a significant positive correlation, with splicing analysis in mESCs displaying highly concordant results. The mESC-based HDR assay showed that the in-frame exon 18 skipping (Δ18) transcript encodes a non-functional protein lacking rescue activity. Linear regression analysis using mESC splicing and functional data indicated that ≥59% of full-length (FL) levels and <34% of Δ18 were associated with benign HDR activity. These thresholds differ from those recommended by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) specifications for applying BP7_strong(RNA): >30% functional transcripts or <70% non-functional transcripts. Incorporation of RNA splicing evidence into variant interpretation increased pathogenic (28.6%-31.7%) and benign (3.7%-24.4%) classifications while reducing likely pathogenic (19.5%-17.7%), uncertain (18.9%-8.5%), and likely benign (29.3%-17.7%) categories. Experimental mRNA profiling impacted the interpretation of 34% of variants and resolved uncertainty in approximately 10% of cases. Exon 18 skipping was less tolerated, indicating that the degree of splice perturbation required to impair BRCA1 function may depend on the nature of the resulting non-functional transcript.

Humans↗

PubMed2026

Germline variants and impact on lung cancer outcomes following chemotherapy: A systematic review.

BACKGROUND: Lung cancer is the primary cause of cancer deaths in the UK and globally, and the main subtypes are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Many treatment options are available, with platinum-based chemotherapy being a key component for many patients. However, variation in survival outcomes exists among individuals of European ancestry, which makes it important to identify germline genetic variants that help guide decision-making and optimise patient treatment and outcomes. METHOD: A systematic literature search was conducted in PubMed and Web of Science for lung cancer studies investigating the impact of germline genetic variants on systemic anti-cancer therapy (SACT) outcomes in populations of European ancestry. The review was conducted according to the Preferred Reporting Items of Systematic Review and Meta-Analysis (PRISMA) and Synthesis without Meta-Analysis (SWiM) guidelines. RESULTS: A total of 20 studies were included in the review out of 4469 on NSCLC and SCLC, encompassing 3639 patients. The most thoroughly investigated area was NSCLC treated with platinum-based chemotherapy. Genetic variants associated with overall survival and/or progression-free survival included XPD Lys751Gln, XPD Asp312Asn, ERCC1 C118T, and XRCC1 Arg399Gln. For non-platinum-treated NSCLC and SCLC, there was insufficient evidence to conduct a meaningful investigation. CONCLUSION: The XPD Lys751Gln, XPD Asp312Asn, ERCC1 C118T, and XRCC1 Arg399Gln variants showed potential associations with survival outcomes among patients of European ancestry with NSCLC after platinum-based chemotherapy. To support clinical implementation, large real-world pharmacogenomics studies stratified by ancestry are needed to overcome statistical power and heterogeneity limitations.

Humans↗

PubMed2026

Impact of BRCA2 pathogenic variants on outcomes to first-line CDK4/6 inhibitors plus endocrine therapy in HR-positive/HER2-negative metastatic breast cancer.

BACKGROUND: Currently, three cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are approved in combination with endocrine therapy (ET) as first-line treatment of patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). The impact of homologous recombination repair (HRR) pathogenic variants (PV) on outcomes with first-line CDK4/6i plus ET in HR-positive/HER2-negative MBC remains uncertain. PATIENTS AND METHODS: We conducted a multicenter, real-world, case-control study including 233 patients with HR-positive/HER2-negative MBC treated with first-line CDK4/6i and ET. Among them, 116 presented HRR PVs and 117 were matched controls with negative germline testing. The primary objective was to compare progression-free survival (PFS) and overall survival among germline-BRCA2 PV carriers, other HRR PV carriers, and controls. To minimize baseline differences in prognostic factors between PV carriers and controls, inverse probability of treatment weighting was applied. Molecular analyses in pre-CDK4/6i samples among patients with BRCA2 PV were carried out, including RAD51-foci, PAM50 intrinsic subtype, and RB1 loss of heterozygosity (LOH). RESULTS: Among the included 233 patients, median age at diagnosis was 45 years (interquartile range 39-56) and 33% had de novo metastatic disease. Primary resistance to adjuvant ET was present in 10% and secondary resistance in 27%. After a median follow-up of 44 months, patients with germline-BRCA2 PVs (n = 67) had significantly shorter PFS [11 versus 27 months; adjusted hazard ratio (aHR) 2.73, 95% confidence interval (CI) 1.65-4.51, P < 0.001] compared with controls. Among patients with endocrine-sensitive disease, germline BRCA2 PV carriers had markedly shorter PFS (median PFS 12 versus 39 months; aHR 4.04; 95% CI 1.82-8.98, P < 0.001). Exploratory analyses revealed RB1 LOH before CDK4/6i-treatment in most evaluable BRCA2 tumors. CONCLUSIONS: BRCA2 PVs were independently associated with poorer outcomes to first-line CDK4/6i plus ET in HR-positive/HER2-negative MBC compared with controls, especially relevant among patients with endocrine-sensitive disease. These findings suggest that patients with a germline PV in BRCA2 may require alternative first-line strategies.

Humans↗

PubMed2024

A germline PDGFRB splice site variant associated with infantile myofibromatosis and resistance to imatinib.

PURPOSE: Infantile myofibromatosis is characterized by the development of myofibroblastic tumors in young children. In most cases, the disease is caused by somatic gain-of-function variants in platelet-derived growth factor (PDGF) receptor beta (PDGFRB). Here, we reported a novel germline intronic PDGFRB variant, c.2905-8G>A, in 6 unrelated infants with multifocal myofibromatosis and their relatives. METHODS: We performed constitutional and tumor DNA and RNA sequencing to identify novel variants, which were subsequently characterized in cellular assays. RESULTS: All patients had multiple skin nodules, 4 had bone lesions, and 2 had aggressive disease with bowel obstruction. The c.2905-8G>A substitution creates an alternative acceptor splice site in intron 21, inserting 2 codons in the PDGFRB transcript. Functional studies revealed that the splice change induced a partial loss of function, contrasting with previously described variants. In 4 tumor samples, we identified a second somatic hit at position Asp850 in PDGFRB exon 18, triggering constitutive receptor activation and resistance to imatinib. In addition to vinblastine and methotrexate, 2 patients received imatinib without objective response. One of them switched to dasatinib with concomitant improvement. CONCLUSION: This splice-site PDGFRB variant favors the development of myofibroma, featuring an acquired oncogenic variant in the same gene and resistance to targeted therapy.

Humans↗

PubMed2026

Optimizing GRIDSS for clinical use: A targeted NGS filtering strategy for germline structural variant detection.

Detecting intermediate-sized structural variants (SVs) remains challenging in diagnostics, as tools for single-nucleotide and copy-number variants, particularly read-depth-based methods, are often insufficient. GRIDSS addresses this gap by integrating paired-end mapping, split-read analysis, and assembly-based approaches. However, its use in targeted sequencing and diagnostic workflows remains complex. NGS panel data from 9726 patients with suspected hereditary cancer were analyzed using GRIDSS. A filtering strategy was developed to prioritize clinically relevant germline SVs. Multiple parameter settings were tested to optimize performance. The initial dataset of 1,307,592 variants was reduced to 89 candidates after applying the selected filtering strategy. Of these, 24 had been previously detected by routine callers and were not further analyzed. Among the remaining 65, 13 were considered likely true positives after visual inspection using IGV. Experimental validation was performed by Sanger/Nanopore long-read sequencing for these variants, all of which were confirmed. Eight were classified as (likely) pathogenic, including two frameshift duplications in MSH6, one splicing variant in BARD1, and five mobile element insertions in APC, BRCA2, and PALB2. Altogether, GRIDSS implementation increased diagnostic yield while maintaining feasibility for diagnostic workflows. Comprehensive workflow scheme for germline structural variant detection and results in our diagnostic setting.

Humans↗

PubMed2026

Hereditary cancer: Germline testing practices across ERN GENTURIS member countries.

Germline genetic testing practices for hereditary cancer vary across the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) member countries. We surveyed experts in genetic testing from 20 EU member countries and Norway to assess multi-gene panel usage, availability of genome-wide sequencing, first-tier testing approaches, implementation of polygenic risk scores, and the roles of non-genetic healthcare professionals. National experts and members of the ERN GENTURIS completed a structured questionnaire covering founder germline pathogenic variants (gPV) testing, panel testing for common genetic tumour risk syndromes, use of whole-exome sequencing (WES) and whole-genome sequencing, polygenic risk score implementation, use of formalin-fixed paraffin-embedded tumour samples, laboratory accreditation, and the clinical roles of physicians, genetic counselors and nurses. Significant inter-country heterogeneity was observed. Most countries rely on next-generation sequencing (NGS) multi-gene panels. Founder gPV testing is first-line in a few high-prevalence populations (e.g., BRCA1/2 founders). All 21 countries offer NGS panel tests for hereditary breast and ovarian cancer, and ≥19 countries do so for colorectal and prostate cancers. However, NGS panel size and gene composition exhibit substantial variability. WES is available in 12 countries on a routine basis. Most countries implemented genetic testing on stored tumour tissue from deceased patients. In all countries, clinical geneticists can order germline genetic tests, and in 9 countries, any physician can do so. These findings show differences in accessibility to germline genetic testing of hereditary cancer in Europe. We propose EU-wide guidance via pathways, standards of care, and sharing of best practices to further optimize access to hereditary cancer genetic molecular diagnostics.

Humans↗

PubMed2026

T-rex: standardized analysis of germline variants in whole-exome sequencing trios.

Whole-exome sequencing (WES) enables the identification of rare germline variants contributing to pediatric diseases. Trio-based sequencing, comparing affected children with their parents, is particularly effective for rare disease genetics. However, WES data analysis requires bioinformatics expertise, varies across institutions, and is often incompatible with clinical workflows. We developed T-Rex (Trio Rare variant analysis of EXomes), a cross-platform desktop application that enables the standardized and local analysis of WES germline Trio data without the need for programming knowledge. T-Rex integrates state-of-the-art tools for alignment, dual-variant calling (GATK HaplotypeCaller + VarScan2), annotation (SNPEff/SNPSift), rare-variant filtering based on population frequencies (gnomAD), and family-based statistical testing, including the Transmission Disequilibrium Test with multiple-testing correction. Benchmarking of the dual-caller strategy on the Genome in a Bottle Ashkenazim Trio demonstrates high precision (99.2%) while maintaining robust sensitivity (91.1%). User testing (n = 13) confirmed quick learning across clinicians and researchers. Application to a cohort of n = 121 pediatric cancer Trio datasets, filtering for rare protein-coding variants (MAF ≤ 0.1% in gnomAD v4.1), validated all assessable previously reported pathogenic variants. Overall, T-Rex enables clinicians to robustly analyze WES Trio data in compliance with data protection regulations without requiring additional software licenses. As one of the first platforms for comprehensive WES Trio analysis that requires no programming expertise while providing reproducible, end-to-end workflows for clinical genomics, T-Rex facilitates collaborative research between clinics and reduces reliance on external providers.

Humans↗

PubMed2025

Clinical characteristic of isolated thrombocytopenia in patients with bone marrow failure-related germline variants: a retrospective study from a single centre.

BACKGROUND: Immune thrombocytopenia (ITP) comprises the majority of thrombocytopenia. Some patients respond poorly to first-line ITP therapy or develop pancytopenia years later. Recent studies link heterozygous germline variants in acquired aplastic anemia (AA), yet their role in isolated thrombocytopenia carrying bone marrow failure-related germline variants (ITGV-BMFs) remains unclear. While whole-exome sequencing (WES) detects these variants, its cost limits routine use. This study compares prognosis and clinical features of isolated thrombocytopenia in patients with ITGV-BMFsand those with classic ITP. METHODS: The clinical data of patients diagnosed with ITGV-BMFs were retrospectively analyzed and compared with those of patients with classic ITP from August 2018 to February 2024. The baseline characteristics, genomic systematically background, previous treatment response as well as their follow-up outcomes were compared. RESULTS: Patients with ITGV-BMFs demonstrated earlier onset age (p < 0.001), lower bleeding scores and CD34%, along with elevated mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and reticulocyte (RET) counts (p < 0.001). Multivariate logistic regression analysis showed that the patients with ITGV-BMFs may possess distinct characteristics, including an earlier age at onset (p = 0.014) and lower bleeding score (p = 0.048). Notably, MCV and RET showed promising performance in receiver operating characteristic (ROC) curve analysis. During the follow-up period, 57.69% (15/26) ITGV-BMFs patients were further confirmed as aplastic anemia (AA, n = 13) or myelodysplastic syndrome (MDS, n = 2), with a median progression-free survival (PFS) of 7.25 years (p < 0.0001). CONCLUSION: ITGV-BMFs may be diagnosed early using elevated MCV and reticulocyte counts, a diagnostic approach that may lead to earlier intervention and improved prognosis.

Humans↗

PubMed2026

WxS-QC-a quality control pipeline for human germline short-variant Whole-Genome and Whole-Exome cohorts for population-scale analyses.

SUMMARY: Whole-exome (WES) and whole-genome (WGS) sequencing are rapidly becoming preferred methods for population-scale analysis of the human genetic landscape. However, there are currently no standardized quality control (QC) pipelines for human WES and WGS datasets. In this paper, we present WxS-QC, a powerful, scalable, and convenient pipeline for the QC of human germline short-variant WGS and WES cohorts for population-scale analyses. Our pipeline is suitable for both rare-variant discovery and common-variant association studies. It is based on deeply refactored gnomAD v3 and v4 quality control pipelines, contains several methods we have developed de novo, and is aligned with current best practices in WGS/WES germline cohort QC. We provide all methods in a single codebase, aligned to work together and controlled via a single YAML config, with automatic export of resulting graphs and summary tables, excellent performance and scalability, and comprehensive documentation. The pipeline can run in any UNIX-like environment and can efficiently process cohorts of up to 200 000 whole-exome samples, with the potential to handle bigger datasets. AVAILABILITY AND IMPLEMENTATION: The pipeline code is written in Python using the Hail library and is freely available under the BSD-3 license here: https://github.com/wtsi-hgi/wxs-qc. The detailed description of the pipeline is available in the pipeline documentation: https://github.com/wtsi-hgi/wxs-qc/blob/main/README.md. We also provide an open dataset with all required metadata, which is available at https://wxs-qc-data.cog.sanger.ac.uk/wxs-qc_public_dataset_v3.tar. An example of test dataset analysis is available in the supplementary materials.

Humans↗

PubMed2019

Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE): a cloud-based platform for curating and classifying germline variants.

Variant interpretation in the era of massively parallel sequencing is challenging. Although many resources and guidelines are available to assist with this task, few integrated end-to-end tools exist. Here, we present the Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE), a web- and cloud-based platform for annotation, identification, and classification of variations in known or putative disease genes. Starting from a set of variants in variant call format (VCF), variants are annotated, ranked by putative pathogenicity, and presented for formal classification using a decision-support interface based on published guidelines from the American College of Medical Genetics and Genomics (ACMG). The system can accept files containing millions of variants and handle single-nucleotide variants (SNVs), simple insertions/deletions (indels), multiple-nucleotide variants (MNVs), and complex substitutions. PeCanPIE has been applied to classify variant pathogenicity in cancer predisposition genes in two large-scale investigations involving >4000 pediatric cancer patients and serves as a repository for the expert-reviewed results. PeCanPIE was originally developed for pediatric cancer but can be easily extended for use for nonpediatric cancers and noncancer genetic diseases. Although PeCanPIE's web-based interface was designed to be accessible to non-bioinformaticians, its back-end pipelines may also be run independently on the cloud, facilitating direct integration and broader adoption. PeCanPIE is publicly available and free for research use.

Child↗

PubMed2026

Novel Germline ELP1 Splice-Acceptor Variant in NF1-Negative Optic Pathway Glioma: Expanding the Clinical Spectrum Associated With ELP1 Variation.

We report a 7-year-old boy with NF1-negative optic pathway glioma harboring a novel germline ELP1 splice-acceptor variant (NM_003640.5:c.2205-2A>G) identified by whole-exome sequencing. The variant was likely pathogenic (ACMG/AMP: PVS1, PM2) and inherited from an asymptomatic father, consistent with incomplete penetrance, expanding the limited evidence linking germline ELP1 variation to gliomas.

Humans↗

PubMed2025

Early germline sequestration in a basidiomycete fungus.

In sexual organisms, inheritance of new mutations is highly dependent on the timing of germline definition. Here, we used the fairy ring-forming fungus Marasmius oreades to challenge the general assumption of a late germline separation in the Fungi. We collected mushrooms from different parts of rings over a 7-year period and identified new mutations in different tissues by whole-genome sequencing. We found evidence that fertile and sterile tissues had accumulated different mutations, suggesting that the germ line, destined for spore production, is already defined in the mycelium in this species. Moreover, the germ line carried fewer mutations than sterile tissues, indicating a lower mutation rate. Our findings suggest that early germline sequestration is more widespread than previously considered across multicellular life.

Genome, Fungal↗

PubMed2026

Updated ENIGMA recommendations for reporting germline variants in cancer susceptibility genes and their translation into twenty languages.

Genetic testing for cancer susceptibility underpins precision cancer prevention and care. Gaps in the healthcare providers' genetic literacy and an ambiguous lexicon for variant description may hinder proper delivery and clinical application of consistently trustworthy test results. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) international consortium supports controlled terminology and recommends a framework for reporting germline variants in cancer susceptibility genes, using breast cancer as an exemplar. Moving forward towards terminological coherence across disciplines and borders, the ENIGMA Clinical Working Group launched a multinational effort to release consortium-approved translations of the published recommendations. The herein reported Vocabulary Translation Project offered an opportunity to reappraise and align the reference text to the recent BRCA1 and BRCA2 specifications to the American College of Medical Genetics and Genomics/Association for Molecular Pathology rules by the ENIGMA Variant Curation Expert Panel and to highlight country-specific differences in breast cancer risk assessment and management. The updated recommendations and their 20 translations are now provided as easy to handle documents, covering 11 of the most widely spoken languages in the world. They will contribute to minimised erroneous inferences, more informed decision-making, improved health outcomes and equity in the use of genetic testing for cancer predisposition and in translational oncology.

Humans↗

PubMed2026

The Clinical Application of Refined Risk Estimates Study in BRCA1 and BRCA2 Pathogenic Variant Carriers: A Randomized Controlled Trial.

UNLABELLED: Individuals with germline BRCA1 or BRCA2 pathogenic variants (PV) may struggle with risk management decision-making. Advancements in technology could provide more specific risk information to patients, but the impact of this information is unknown. The Clinical Application of Refined Risk Estimates Study is a two-arm randomized controlled trial in women with a BRCA1/BRCA2 PV. The primary objective was to determine whether genotype-informed personalized cancer risk estimates (GRE) compared with standard lifetime cancer risk estimates (SRE) decreased decisional conflict related to cancer risk management decision-making. Women were recruited following the disclosure of their PV results. Participants completed a baseline survey and were randomized 1:1 to receive a GRE or SRE. After receiving their results, participants completed a follow-up survey. Likert and continuous data measures were analyzed using linear regression. There were no differences in decisional conflict between study arms at follow-up. However, individuals in the SRE arm showed an increased need for personal structure compared with those in the GRE arm (P = 0.02). Compared with baseline, individuals within the SRE arm showed decreased decisional conflict (P = 0.003) and increased perceived stress (P = 0.02) at follow-up. A more personalized cancer risk estimate did not decrease decisional conflict in women with BRCA1/BRCA2 PVs. Future studies will determine whether a GRE affects actual decision-making behaviors. PREVENTION RELEVANCE: Women with a germline PV in BRCA1 or BRCA2 have significantly elevated risks of developing breast and ovarian cancers. This randomized controlled trial evaluates the impact of polygenic risk scores on decisional conflict related to breast and ovarian cancer prevention and risk management in those with BRCA1/BRCA2 PVs.

Humans↗

PubMed2026

Identification of Rare Noncoding Variants in Familial Nonmedullary Thyroid Carcinoma.

BACKGROUND: Familial nonmedullary thyroid carcinoma (FNMTC) occurs when three or more family members are affected by usually papillary thyroid carcinoma (PTC), the most common form of NMTC. While the heritability to NMTC is among the highest of all cancers, the genetic determinants among NMTC families are not well understood. Here, we aim to understand the contribution of rare noncoding germline variants in the etiology of FNMTC. METHODS: We previously reported whole-genome sequencing (WGS) and linkage analysis in 17 PTC families and reported on 41 protein-coding variants in 40 genes that cosegregated with PTC in 11 of the families. Herein, we further leveraged our WGS data to include noncoding variants in our analysis for all 17 families. We hypothesized that most of the pathogenic noncoding variants would be located in theoretical or empirically determined regulatory regions that demonstrate at a minimum, basal thyroid expression, a positive family linkage score, and co-segregation among PTC-affected individuals. To test this hypothesis, we adopted a unique filtering strategy to identify variants that occurred in known DNA elements and transcription factor binding sites, near regions known to impact on gene expression or splicing in thyroid tissue, and/or in characterized thyroid enhancers. We annotated variants using two analyses (ENCODE and transcription factor binding site) within the BasePlayer software. We separately analyzed (1) expression quantitative trait loci, (2) splicing quantitative trait loci, and (3) thyroid enhancers. We then ranked variants according to predicted pathogenicity and performed Sanger sequencing in all individuals of each family. RESULTS: In total, 121 variants were selected based on in-silico prediction and our custom ranking analysis in each pedigree. Of these, 56 variants showed cosegregation among all PTC-affected individuals and were absent from unaffected individuals. This included candidate variants from five of the six PTC families for whom no protein-coding variants were previously found. CONCLUSION: Our data suggest that noncoding variants are important in the etiology of FNMTC and provide a framework for identifying noncoding germline variants using a novel approach. Further studies are needed to functionally characterize these variants to better understand the molecular mechanism of their pathogenicity.

Humans↗