Patterns and functional implications of rare germline variants across 12 cancer types

Large-scale cancer sequencing data enable discovery of rare germline cancer susceptibility variants. Here we systematically analyse 4,034 cases from The Cancer Genome Atlas cancer cases representing 12 cancer types. We find that the frequency of rare germline truncations in 114 cancer-susceptibility-associated genes varies widely, from 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high frequency of 11% in stomach cancer. Burden testing identifies 13 cancer genes with significant enrichment of rare truncations, some associated with specific cancers (for example, RAD51C, PALB2 and MSH6 in AML, stomach and endometrial cancers, respectively). Significant, tumour-specific loss of heterozygosity occurs in nine genes (ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2 and RAD51C/D). Moreover, our homology-directed repair assay of 68 BRCA1 rare missense variants supports the utility of allelic enrichment analysis for characterizing variants of unknown significance. The scale of this analysis and the somatic-germline integration enable the detection of rare variants that may affect individual susceptibility to tumour development, a critical step toward precision medicine. Published sequencing data sets of cancer samples could be used to identify genetic variants associated with the risk of developing cancer. Here, Luet al. analyse over 4,000 tumour-normal pairs to reveal variable frequencies of inherited susceptibilities across 12 cancer types and find enrichment of functionally validated missense variants of unknown significance.

• Publication year

  2015

• Venue

  Nature Communications

• Publication date

  2015-12-22

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/ncomms10086PMID 26689913PMCID 4703835
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Predicting Prognosis of Early-Stage Non-Small Cell Lung Cancer Using the GeneFx® Lung Signature

  2015cited by this paper
• Age-related cancer mutations associated with clonal hematopoietic expansion

  2014cited by this paper
• Summary and discussion of : “ Controlling the False Discovery Rate : A Practical and Powerful Approach to Multiple Testing

  2014cited by this paper
• Discovery and saturation analysis of cancer genes across 21 tumor types

  2014cited by this paper
• Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation, and gene rearrangement in clinical cancer specimens.

  2014cited by this paper
• Realizing the promise of cancer predisposition genes

  2014influential reference
• Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin.

  2014cited by this paper
• Most common 'sporadic' cancers have a significant germline genetic component.

  2014cited by this paper
• Mutational landscape and significance across 12 major cancer types

  2013cited by this paper
• Comprehensive molecular portraits of human breast tumours

  2013cited by this paper
• Identification and Biochemical Characterization of a Novel Mutation in DDX11 Causing Warsaw Breakage Syndrome

  2013cited by this paper
• Genetic Testing Strategies in Newly Diagnosed Endometrial Cancer Patients Aimed at Reducing Morbidity or Mortality from Lynch Syndrome in the Index Case or Her Relatives

  2013cited by this paper
• Cancer Genome Landscapes

  2013cited by this paper
• Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing

  2013cited by this paper
• ACMG clinical laboratory standards for next-generation sequencing

  2013cited by this paper
• MuSiC: Identifying mutational significance in cancer genomes

  2012cited by this paper
• Comprehensive molecular portraits of human breast tumors

  2012cited by this paper
• ATM gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression

  2012cited by this paper
• VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing.

  2012cited by this paper
• Genetic epidemiology of cigarette smoke-induced lung disease.

  2012cited by this paper
• GWAS Integrator: a bioinformatics tool to explore human genetic associations reported in published genome-wide association studies

  2011cited by this paper
• Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing

  2011cited by this paper
• Comparison of statistical tests for disease association with rare variants

  2011cited by this paper
• Allelic Selection of Amplicons in Glioblastoma Revealed by Combining Somatic and Germline Analysis

  2010cited by this paper
• The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.

  2010cited by this paper
• Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients.

  2010cited by this paper
• Nature Communications

  2010cited by this paper
• Identification of breast tumor mutations in BRCA1 that abolish its function in homologous DNA recombination.

  2010cited by this paper
• Rare genetic variants and the risk of cancer.

  2010cited by this paper
• PALB2 is an integral component of the BRCA complex required for homologous recombination repair

  2009cited by this paper
• Four novel germline mutations in the MLH1 and PMS2 mismatch repair genes in patients with hereditary nonpolyposis colorectal cancer

  2009cited by this paper
• ATM activates p53 by regulating MDM2 oligomerization and E3 processivity

  2009cited by this paper
• Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads

  2009cited by this paper
• Evaluation of BRCA1 and BRCA2 mutations and risk-prediction models in a typical Asian country (Malaysia) with a relatively low incidence of breast cancer

  2008cited by this paper
• The Fanconi anemia protein FANCM can promote branch migration of Holliday junctions and replication forks.

  2008cited by this paper
• Oncogenic CARD11 Mutations in Human Diffuse Large B Cell Lymphoma

  2008cited by this paper
• Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants?

  2007cited by this paper
• A strategy to discover genes that carry multi-allelic or mono-allelic risk for common diseases: a cohort allelic sums test (CAST).

  2007cited by this paper
• The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen

  2006cited by this paper
• Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years.

  2006cited by this paper
• BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases

  2005cited by this paper
• Understanding the function–structure and function–mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis

  2003cited by this paper
• Repeated observation of breast tumor subtypes in independent gene expression data sets

  2003cited by this paper
• Aberrant splicing induced by missense mutations in BRCA1: clues from a humanized mouse model.

  2003cited by this paper
• Twenty‐three novel BRCA1 and BRCA2 sequence alterations in breast and/or ovarian cancer families in Southern Germany

  2003cited by this paper
• Detection of Protein Folding Defects Caused by BRCA1-BRCT Truncation and Missense Mutations*

  2003cited by this paper
• Ku DNA end-binding protein modulates homologous repair of double-strand breaks in mammalian cells.

  2001cited by this paper
• Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer.

  2001cited by this paper
• The p53 mutational spectrum associated with BRCA1 mutant ovarian cancer.

  2001cited by this paper
• Functional assay for BRCA1: mutagenesis of the COOH-terminal region reveals critical residues for transcription activation.

  2000cited by this paper
• Frequent allelic imbalance suggests involvement of a tumor suppressor gene at 1p36 in the pathogenesis of human lung cancers

  2000cited by this paper
• The Breast Cancer Information Core: Database design, structure, and scope

  2000cited by this paper
• Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland.

  2000cited by this paper
• Allelic imbalance and mutations of the PTEN gene in ovarian cancer

  2000cited by this paper
• BRCA1, BRCA2, and Hereditary Nonpolyposis Colorectal Cancer Gene Mutations in an Unselected Ovarian Cancer Population: Relationship to Family History and Implications for Genetic Testing

  1998cited by this paper
• BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in an unselected ovarian cancer population: relationship to family history and implications for genetic testing.

  1998cited by this paper
• BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression

  1998cited by this paper
• Controlling the false discovery rate: a practical and powerful approach to multiple testing

  1995cited by this paper
• Biometry: the principles and practice of statistics in biological research 2nd edition.

  1981cited by this paper
• Mutation and cancer: statistical study of retinoblastoma.

  1971cited by this paper
• Biometry: The Principles and Practice of Statistics in Biological Research

  1969cited by this paper
• Statistical methods for research workers

  1927cited by this paper
• Probable Inference, the Law of Succession, and Statistical Inference

  1927cited by this paper

• Genetic Basis of Familial Cancer Risk: A Narrative Review

  2026cites this paper
• Global analysis of actionable genomic alterations in thyroid cancer and precision-based pharmacogenomic strategies

  2025cites this paper
• Targeting the CD74 signaling axis suppresses inflammation and rescues defective hematopoiesis in RUNX1-familial platelet disorder.

  2025cites this paper
• Exploring the link between low germline mutational load and low breast cancer incidence: Lessons from the Xavante Indians

  2025cites this paper
• High-throughput evaluation of in vitro CRISPR activities enables optimized large-scale multiplex enrichment of rare variants.

  2025cites this paper
• The Prognostic and Predictive Roles of Ataxia–Telangiectasia Mutated (ATM) Expression in Patients with Metastatic Non-Small-Cell Lung Cancer Receiving Pembrolizumab Monotherapy Alone or in Combination with Chemotherapy

  2025cites this paper
• Pathogenic germline variants in Chinese pancreatic adenocarcinoma patients

  2025cites this paper
• Precision proteogenomics reveals pan-cancer impact of germline variants.

  2025cites this paper
• Genomic evolution of high-risk soft tissue sarcomas under thermo- and chemotherapeutic selection pressure

  2025cites this paper
• Analysis of germline-somatic mutational connections in colorectal cancer reveals differential tumorigenic patterns and a novel predictive marker for germline mutation carriers.

  2025cites this paper
• The role of multi-organ cancer predisposition genes in the risk of inherited and histologically diverse gastric cancer

  2025cites this paper
• Comprehensive genomic profiling of Chinese lung cancer characterizes germline-somatic mutation interactions influencing cancer risk

  2025influential citation
• The landscape of germline variants in breast and colorectal cancer susceptibility genes in patients with pituitary tumours

  2025cites this paper
• Germline variant spectrum of hereditary cancer susceptibility genes in a Chinese cohort

  2025cites this paper
• Genomic Profiling of Cardiac Angiosarcoma Reveals Novel Targetable KDR Variants, Recurrent MED12 Mutations and a High Burden of Germline POT1Alterations.

  2025cites this paper
• Germline Variations in Patients With Oral Squamous Cell Carcinoma-Systematic Review.

  2025cites this paper
• Molecular and clinical insights into early-onset endometrial cancer.

  2025cites this paper
• MSH6 gene methylation on clinical pathology and diagnosis in retinoblastoma: a bioinformatics analysis.

  2025cites this paper
• Characteristics of Gene Mutations in Lung Cancer Patients in Southwest China and Analysis of Their Correlation with Clinical Features

  2025cites this paper
• Differences of clinical features, prognosis and genetic mutations in Chinese patients with malignant melanoma and additional primary tumours

  2025influential citation
• Functional characterization of BRCA1 variants of unknown significance using homologous recombination repair assays

  2025cites this paper
• Phase 1 clinical trial of the ataxia telangiectasia and Rad3‐related inhibitor berzosertib with irinotecan in patients with advanced solid tumors (ETCTN 9938)

  2025cites this paper
• High-resolution functional mapping of RAD51C by saturation genome editing.

  2024cites this paper
• Gender-Specific Genetic Predisposition to Breast Cancer: BRCA Genes and Beyond

  2024cites this paper
• PMS2CL interference leading to erroneous identification of a pathogenic PMS2 variant in Black patients

  2024cites this paper
• Impact of genomic and epigenomic alterations of multigene on a multicancer pedigree

  2024cites this paper
• The Molecular Detection of Germline Mutations in the BRCA1 and BRCA2 Genes Associated with Breast and Ovarian Cancer in a Romanian Cohort of 616 Patients

  2024cites this paper
• In Silico Prediction of BRCA1 and BRCA2 Variants with Conflicting Clinical Interpretation in a Cohort of Breast Cancer Patients

  2024cites this paper
• Characterization of Incidental Pathogenic Germline Findings Detected via ctDNA among Patients with Non-Small Cell Lung Cancer in a Predominantly Hispanic/Latinx Population

  2024cites this paper
• Analysis of 3760 hematologic malignancies reveals rare transcriptomic aberrations of driver genes

  2024cites this paper
• Worldwide analysis of actionable genomic alterations in lung cancer and targeted pharmacogenomic strategies

  2024cites this paper
• Germline RAD51C and RAD51D Mutations in High-Risk Chinese Breast and/or Ovarian Cancer Patients and Families

  2024cites this paper
• Association of XRCC2 with breast cancer, a multi-omics analysis at genomic, transcriptomic, and epigenomic level.

  2024cites this paper
• Germline predisposition in multiple myeloma

  2024cites this paper
• XRCC2 Gene Study by Next Generation Sequencing and Establishing Its Relation with Breast Cancer

  2024cites this paper
• The pathogenic germline ETV4 P433L mutation identified in multiple primary lung cancer affect tumor stem-like property by Wnt/β-catenin pathway

  2024influential citation
• Single nucleotide variants in lung cancer

  2024cites this paper
• Gastric cancer actionable genomic alterations across diverse populations worldwide and pharmacogenomics strategies based on precision oncology

  2024cites this paper
• Safety and efficacy of canakinumab treatment for undifferentiated autoinflammatory diseases: the data of a retrospective cohort two-centered study

  2023cites this paper
• Impact of genetic counselling strategy on diagnostic yield and workload for genome sequencing-based tumour diagnostics.

  2023cites this paper
• European standard clinical practice - Key issues for the medical care of individuals with familial leukemia.

  2023cites this paper
• Comprehensive Analysis of Germline Drivers in Endometrial Cancer.

  2023cites this paper
• Clinical features and prognosis of double primary malignant neoplasms in patients with non-hodgkin lymphoma

  2023cites this paper
• ATM—the gene at the moment in non-small cell lung cancer

  2023cites this paper
• Second primary malignancies in non-Hodgkin lymphoma: epidemiology and risk factors

  2023cites this paper
• Functional Analyses of Rare Germline Missense BRCA1 Variants Located within and outside Protein Domains with Known Functions

  2023cites this paper
• A homozygous truncating ETV4 variant in a Nigerian family with congenital anomalies of the kidney and urinary tract

  2023cites this paper
• Association of Reported Candidate Monogenic Genes With Lung Cancer Risk.

  2023cites this paper
• Analysis of clinical and genomic profiles of therapy-related myeloid neoplasm in Korea

  2023cites this paper
• Early-Onset Ovarian Cancer <30 Years: What Do We Know about Its Genetic Predisposition?

  2023cites this paper
• Impact of genetic counselling strategy on diagnostic yield and workload for whole genome sequencing-based tumour diagnostics

  2023cites this paper
• Comprehensive genomic profiling of breast cancers characterizes germline-somatic mutation interactions mediating therapeutic vulnerabilities

  2023cites this paper
• Prevalence of BRCA1 and BRCA2 germline variants in an unselected pancreatic cancer patient cohort in Pakistan

  2023cites this paper
• Identification of pathogenic germline variants in a large Chinese lung cancer cohort by clinical sequencing

  2023influential citation
• Risk for Hereditary Neoplastic Syndromes in Women with Mismatch Repair-Proficient Endometrial Cancer

  2023cites this paper
• Angioimmunoblastic T‐cell lymphoma: Novel recurrent mutations and prognostic biomarkers by cell‐free DNA profiling

  2023cites this paper
• A Novel Germline Mutation of BRCA1 and Integrated Analysis With Somatic Mutation in a Chinese Multi-Cancer Family

  2023cites this paper
• Multiplexed assay of variant effect reveals residues of functional importance in the BRCA1 coiled-coil and serine cluster domains

  2023cites this paper
• Challenges associated with the identification of germline variants on myeloid malignancy genomic profiling—a Singaporean experience

  2023cites this paper
• Germline mutations in the PALB2 and CHEK2 genes and hereditary cancer

  2023cites this paper
• Reduced FANCE Confers Genomic Instability and Malignant Behavior by Regulating Cell Cycle Progression in Endometrial Cancer

  2023cites this paper
• Rare variants confer shared susceptibility to gastrointestinal tract cancer risk

  2023cites this paper
• Actionability classification of variants of unknown significance correlates with functional effect

  2023cites this paper
• Partner and localizer of BRCA2 (PALB2) pathogenic variants and ovarian cancer: A systematic review and meta-analysis.

  2023cites this paper
• Hereditary Gastric Cancer: Single-Gene or Multigene Panel Testing? A Mono-Institutional Experience

  2023cites this paper
• Germline EGFR mutations in lung cancer (Review)

  2023cites this paper
• Somatic and germline ATM variants in non-small-cell lung cancer: Therapeutic implications.

  2023cites this paper
• Identifying patients at risk for hereditary myeloid malignancy syndromes incorporating a novel, self‐administered questionnaire to an initial screening platform

  2023cites this paper
• The Clinical Spectrum, Diagnosis, and Management of GATA2 Deficiency

  2023cites this paper
• Functional analyses of rare germline BRCA1 variants by transcriptional activation and homologous recombination repair assays

  2023cites this paper
• Immunogenicity of Cemiplimab: Low Incidence of Antidrug Antibodies and Cut‐Point Suitability Across Tumor Types

  2023cites this paper
• Germline mutations in high penetrance genes are associated with worse clinical outcomes in patients with non–small cell lung cancer

  2022cites this paper
• Minimal information for reporting a genomics experiment

  2022cites this paper
• Analysis of rare disruptive germline mutations in 2,135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes.

  2022cites this paper
• Familial history and prevalence of BRCA1, BRCA2 and TP53 pathogenic variants in HBOC Brazilian patients from a public healthcare service

  2022cites this paper
• Diagnostic yield and clinical relevance of expanded genetic testing for cancer patients

  2022cites this paper
• A common pathway to cancer: Oncogenic mutations abolish p53 oscillations.

  2022cites this paper
• Sigma70Pred: A highly accurate method for predicting sigma70 promoter in Escherichia coli K-12 strains

  2022cites this paper
• Case report: Mesothelioma and BAP1 tumor predisposition syndrome: Implications for public health

  2022cites this paper
• Germline Testing for the Evaluation of Hereditary Cancer Predisposition.

  2022cites this paper
• Stem cell architecture drives myelodysplastic syndrome progression and predicts response to venetoclax-based therapy

  2022cites this paper
• Homologous Recombination Deficiency in Ovarian, Breast, Colorectal, Pancreatic, Non-Small Cell Lung and Prostate Cancers, and the Mechanisms of Resistance to PARP Inhibitors

  2022cites this paper
• The functional impact of BRCA1 BRCT domain variants using multiplexed DNA double-strand break repair assays.

  2022cites this paper
• Solving the genetic aetiology of hereditary gastrointestinal tumour syndromes- a collaborative multicentre endeavour within the project Solve-RD.

  2022cites this paper
• TP53_PROF: a machine learning model to predict impact of missense mutations in TP53

  2022cites this paper
• BRCA1/2 variants of unknown significance in hereditary breast and ovarian cancer (HBOC) syndrome: looking for the hidden meaning.

  2022cites this paper
• Integrative analysis of genomic and transcriptomic data of normal, tumour, and co‐occurring leukoplakia tissue triads drawn from patients with gingivobuccal oral cancer identifies signatures of tumour initiation and progression

  2022cites this paper
• Gastric Cancer Risk and Pathogenesis in BRCA1 and BRCA2 Carriers

  2022cites this paper
• A structural variation genotyping algorithm enhanced by CNV quantitative transfer

  2022cites this paper
• Germline CHEK2 and ATM Variants in Myeloid and Other Hematopoietic Malignancies

  2022cites this paper
• Germline Predisposition in AML

  2021cites this paper
• CMAR_A_311548 4351..4357

  2021cites this paper
• Germline rare deleterious variant load alters cancer risk, age of onset and tumor characteristics

  2021cites this paper
• Screening of DNA Damage Repair Genes Involved in the Prognosis of Triple-Negative Breast Cancer Patients Based on Bioinformatics

  2021cites this paper
• A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and Confers a Targetable Defect in Homologous Recombination Repair

  2021cites this paper
• The Functional Hallmarks of Cancer Predisposition Genes

  2021cites this paper
• Exonic variants undergoing allele-specific selection in cancers

  2021cites this paper
• BRCA1/BRCA2 variants of uncertain significance in clinical practice: A case report.

  2021cites this paper
• Familial Occurrence of Adult Granulosa Cell Tumors: Analysis of Whole-Genome Germline Variants

  2021cites this paper
• Sigma70Pred: A highly accurate method for predicting sigma70 promoter in prokaryotic genome

  2021cites this paper