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BackgroundThe strength of evidence supporting the validity of gene-disease relationships is variable. Hereditary cancer has the additional complexity of low or moderate penetrance for some confirmed disease-associated alleles.MethodsTo promote national consistency in interpretation of hereditary cancer/tumour gene test results, we requested opinions of representatives from Australian Family Cancer Clinics regarding the clinical utility of 157 genes initially collated for a national research project. Viewpoints were sought by initial survey, face-to-face workshop and follow-up survey. Subsequent review was undertaken by the eviQ Cancer Genetics Reference Committee, a national resource providing evidence-based and consensus-driven cancer treatment protocols.ResultsGenes were categorised by clinical actionability as: relevant for testing on presentation of common cancer/tumour types (n=45); relevant for testing in the context of specific rare phenotypes (n=74); insufficient clinical utility (n=34) or contentious clinical utility (n=3). Opinions for several genes altered during the study time frame, due to new information.ConclusionThrough an iterative process, consensus was achieved on genes with clinical utility for hereditary cancer/tumour conditions in the Australian setting. This study highlighted need for regular review of gene-disease lists, a role assumed in Australia for hereditary cancer/tumour predisposition genes by the eviQ Cancer Genetics Reference Committee.

Germline variants in RUNX1, GATA2 and DDX41 may confer a predisposition to hereditary haematopoietic malignancies (HHMs) such as MDS and AML yet have distinct age ranges of malignancy diagnosis and a highly variable overall risk for leukemogenesis. The increased awareness and identification of carriers of these germline variants, particularly before development of malignancy, has changed the way in which individuals and families need to be managed in the clinic. Individuals need lifelong monitoring and may also need modification to treatments when malignancy does develop, compared to sporadic counterparts. Gaps in understanding pre-malignant states in HHM syndromes have hampered efforts to design effective clinical surveillance regimes, provide personalized pre-emptive treatments, and appropriate counselling to patients.

Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p 0 center dot 0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and onlyBackground Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Interpretation Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding National Health and Medical Research Council, Australia. Copyright (c) 2021 Elsevier Ltd. All rights reserved.Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.

Most patients with Cowden syndrome have lesions in the gastrointestinal tract, characterized by multiple polyps of various histologic types in the large bowel, polyps in the upper gastrointestinal tract, and esophageal glycogenic acanthosis. However, pathologists are often unaware of the distinctive polyposis phenotype of Cowden syndrome. In this multicenter study, we report the spectrum of gastrointestinal manifestations in a series of 43 Cowden syndrome patients who had at least one endoscopy. The median age at the first endoscopy was 46 years and 58% were women. In 24 of 29 (83%) tested patients, a pathogenic germline mutation in PTEN was identified. The histology from 199 endoscopy procedures (67 upper gastrointestinal endoscopy and 132 colonoscopies) was reviewed. Hamartomatous polyps of the large bowel were the most common lesions, present in 85% of patients. Hamartomatous polyps showed varied histology, including lymphoid aggregates in 55% of patients, a lipomatous component in 52%, a ganglioneuromatous component in 52%, and a fibrous-rich component in 14%. Polyps with at least two different stromal components were found in 55% of patients. Inflammatory polyps were present in 21% of patients. Conventional adenomas and serrated polyps were identified in 48% and 62% of patients, respectively. In the upper gastrointestinal tract, the most common lesions were esophageal glycogenic acanthosis (37%), gastric hamartomatous polyps (47%), and duodenal hamartomatous polyps (20%). All patients with glycogenic acanthosis who had a colonoscopy had hamartomatous polyps of the large bowel. In five patients, the diagnosis of Cowden syndrome was established after the pathology report raised suspicion for the diagnosis. Pathologists who are aware of the characteristic admixture of lesions in Cowden syndrome can play an essential role in recommending referral to genetic counseling and gene testing. Early diagnosis of Cowden syndrome is important, as these patients and their relatives are at increased risk for developing multiple cancers.

In patients with early breast cancer, personal and tumour characteristics other than family history are increasingly used to prompt genetic testing to guide women’s cancer management (treatment-focused genetic testing, ‘TFGT’). Women without a known strong family history of breast and/or ovarian may be more vulnerable to psychological sequelae arising from TFGT. We compared the impact of TFGT in women with (FH+) and without (FH−) a strong family history on psychological adjustment and surgical decisions. Women aged

Publisher's version (útgefin grein)., Background: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations. Objective: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status. Design, setting, and participants: Men aged 40–69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy. Outcome measurements and statistical analysis: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians. Results and limitations: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p = 0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p = 0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p = 0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at biopsy than PSA alone (AUC = 0.65). Conclusions: After 3 yr of screening, compared with noncarriers, BRCA2 mutation carriers were associated with a higher incidence of PrCa, younger age of diagnosis, and clinically significant tumours. Therefore, systematic PSA screening is indicated for men with a BRCA2 mutation. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers. Patient summary: We demonstrate that after 3 yr of prostate-specific antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than in those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening. © 2019 The Authors We demonstrate that after 3 yr of prostate-specific-antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening., We demonstrate that, after four annual PSA screening rounds, BRCA2 mutation carriers have a higher incidence of PrCa, are diagnosed at a younger age, and present with more clinically significant tumours than BRCA2 noncarriers. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers. Therefore, these data support the use of systematic PSA screening in male BRCA2 carriers. Author contributions : Rosalind A. Eeles had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design : Aaronson, Ardern-Jones, Bancroft, Bangma, Castro, Dearnaley, Eccles, Evans, Eyfjord, Falconer, Foster, Gronberg, Hamdy, Johannsson, Khoo, Kote-Jarai, Lilja, Lindeman, Lubinski, Mahle, Mikropoulos, Mitra, Moynihan, Page, Rennert, Suri. Acquisition of data: All authors. Analysis and interpretation of data: All authors. Drafting of the manuscript: All authors. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis : Page, Bancroft, Brook, Assel, Vickers, Lilja. Obtaining funding : Eeles and all IMPACT collaborating sites obtained their own funding for running the study at their site. Administrative, technical, or material support: All authors. Supervision: Eeles. Other : None. Financial disclosures: Rosalind A. Eeles certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Hans Lilja holds patents for intact PSA assays, and is named, along with Andrew J. Vickers, on a patent application for a statistical method to detect prostate cancer. The patents have been licensed and commercialised as the 4 Kscore by OPKO Health. Drs. Vickers and Lilja receive royalties from sales of this test. Additionally, Dr. Lilja owns stock and Dr. Vickers owns stock options in OPKO. Professor Rosalind Eeles: Royal Marsden Hospital—Nov 2017; support from Janssen; honorarium as speaker £1100; University of Chicago invited talk May 2018; honorarium as speaker Rosalind A. Eeles certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Hans Lilja holds patents for intact PSA assays, and is named, along with Andrew J. Vickers, on a patent application for a statistical method to detect prostate cancer. The patents have been licensed and commercialised as the 4 Kscore by OPKO Health. Drs. Vickers and Lilja receive royalties from sales of this test. Additionally, Dr. Lilja owns stock and Dr. Vickers owns stock options in OPKO. Professor Rosalind Eeles: Royal Marsden Hospital—Nov 2017; support from Janssen; honorarium as speaker £1100; University of Chicago invited talk May 2018; honorarium as speaker $1000. The remaining authors have no other conflict of interest to declare.000. The remaining authors have no other conflict of interest to declare. Funding/Support and role of the sponsor : This research is coordinated by the Institute of Cancer Research, London, UK, and is supported by grants from Cancer Research UK (grant references C5047/A21332, C5047/A13232, and C5047/A17528) and the Ronald and Rita McAulay Foundation. Judith Offman is supported by Cancer Research UK Programme Grant reference C8161/A16892. Mr. and Mrs. Jack Baker are acknowledged for supporting the study in NorthShore University HealthSystem, Evanston, IL, USA and Myriad Genetics Laboratory, Salt Lake City, UT, USA, for providing research BRCA testing rates for NorthShore University HealthSystem patients. We acknowledge funding from the National Institute for Health Research (NIHR) to the Biomedical Research Center at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, at Manchester University Foundation Trust (IS-BRC-1215-20007), the Oxford Biomedical Research Centre Program, and the Cambridge Clinical Research Centre, NIHR Cambridge Biomedical Research Centre. We acknowledge that in Australia, this project was cofunded by Cancer Council Tasmania and Cancer Australia (grant number 1006349 [2011–2013]), Prostate Cancer Foundation of Australia (grant number PCFA PRO4 [2008]), Cancer Councils of Victoria and South Australia (grant number 400048 [2006–2008]), the Victorian Cancer Agency Clinical Trial Capacity CTCB08_14, Cancer Australia and Prostate Cancer Foundation of Australia (2014–2016; grant number 1059423), and Translational grants EOI09_50. The Association of International Cancer Research funded data collection in The Netherlands (AICR 10-0596). We acknowledge funding from the Basser Center for BRCA (to Susan Domchek). This work was supported in part by the National Institutes of Health/National Cancer Institute (NIH/NCI) with a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center (P30 CA008748), a SPORE grant in Prostate Cancer to Dr. H. Scher (P50-CA92629), the Sidney Kimmel Center for Prostate and Urologic Cancers, David H. Koch through the Prostate Cancer Foundation. This work was also supported in part by the NIHR Oxford Biomedical Research Centre Program in UK, the Swedish Cancer Society (CAN 2017/559), the Swedish Research Council (VR-MH project no. 2016-02974), and General Hospital in Malmö Foundation for Combating Cancer. We acknowledge funding from the Slovenian Research Agency, Research programme P3-0352. We thank CERCA Program/Generalitat de Catalunya for their institutional support. Elena Castro acknowledges funding from Prostate Cancer Foundation. We acknowledge the support of the Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economía y Competitividad), “Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa” (PI10/01422, PI13/00285, PIE13/00022, PI16/00563, JR18/00011 and CIBERONC), and the Institut Català de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338 and PERIS Project MedPerCan). We acknowledge funding support from Fundação para a Ciência e a Tecnologia to the IPO Porto study (project grant PTDC/DTP-PIC/1308/2014 to Manuel R. Teixeira and fellowship grant SFRH/BD/116557/2016 to Marta Cardoso).

First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification., Ohio State University Comprehensive Cancer Center Barretos Cancer Hospital. Grant Number: FINEP ‐ CT‐INFRA (02/2010) Breast Cancer Foundation of New Zealand Canadian Institutes of Health Research. Grant Number: PSR‐SIIRI‐701 Cancer Research UK. Grant Numbers: C8197/A16565, C5047/A8384, C1281/A12014, C12292/A11174, C1287/A10710, C1287/A10118, C1287/A16563, C5047/A10692, C5047/A15007 Department of Defence, USA. Grant Number: W81XWH‐10‐1‐0341 Helsinki University Hospital Research fund Scientific Foundation Asociación Española Contra el Cáncer Leiden University Medical Centre. Grant Number: Grant 30.925 Generalitat de Catalunya. Grant Numbers: PERIS_MedPerCan, URDCat, 2017SGR1282, 2017SGR496 Royal Society of New Zealand Cancer Council Victoria Netherlands Organization for Scientific Research (NWO). Grant Number: Grant 017.008.022 Breast Cancer Research Foundation Cancer Foundation of Western Australia EU H2020. Grant Number: 634935 Fundación Mutua Madrileña Seventh Framework Programme. Grant Numbers: 634935, 223175, 633784 Cancer Council South Australia Government of Galicia. Grant Number: Consolidation and structuring program: IN607B Cancer Council Tasmania Italian Association of Cancer Research. Grant Number: 15547 Queensland Cancer Fund AstraZeneca National Institute of Health (USA). Grant Numbers: 1U19 CA148065‐01, CA128978, CA192393, 1U19 CA148537, P50 CA1162091, CA116167, 1U19 CA148112 Newcastle University Dutch Cancer Society KWF. Grant Numbers: KWF/Pink Ribbon‐11704, UL2012‐5649 National Institute for Health Research. Grant Number: Manchester Biomedical Research centre (IS‐BRC‐1215 National Council of Technological and Scientific Development (CNPq) Instituto de Salud Carlos III. Grant Numbers: FIS PI15/00355, FIS PI13/01711, CIBERONC, FIS PI16/01218, PI16/00563 French National Institute of Cancer National Breast Cancer Foundation National Health and Medical Research Council. Grant Numbers: ID1061778, ID1104808 Carlos III National Health Centro de Investigación Biomédica en Red de Enferemdades Raras. Grant Number: ACCI 2016: ER17P1AC7112/2018 Cancer Council NSW Deutsche Krebshilfe. Grant Numbers: (#110837, #70111850 Fondazione Pisa. Grant Number: Grant “Clinical characterization of BRCA 1/2 Mis

Background We report a kindred referred for molecular investigation of severe hemophilia A in a young female in which extremely skewed X‐inactivation was observed in both the proband and her clinically normal mother. Methods Bidirectional Sanger sequencing of all F8 gene coding regions and exon/intron boundaries was undertaken. Methylation‐sensitive restriction enzymes were utilized to investigate skewed X‐inactivation using both a classical human androgen receptor (HUMARA) assay, and a novel method targeting differential methylation patterns in multiple informative X‐chromosome SNPs. Illumina Whole‐Genome Infinium microarray analysis was performed in the case‐parent trio (proband and both parents), and the proband's maternal grandmother. Results The proband was a cytogenetically normal female with severe hemophilia A resulting from a heterozygous F8 pathogenic variant inherited from her similarly affected father. No F8 mutation was identified in the proband's mother, however, both the proband and her mother both demonstrated completely skewed X‐chromosome inactivation (100%) in association with a previously unreported 2.3 Mb deletion at Xp22.2. At least three disease‐associated genes (FANCB,AP1S2, and PIGA) were contained within the deleted region. Conclusions We hypothesize that true “extreme” skewing of X‐inactivation (≥95%) is a rare occurrence, but when defined correctly there is a high probability of finding an X‐chromosome disease‐causing variant or larger deletion resulting in X‐inactivation through a survival disadvantage or cell lethal mechanism. We postulate that the 2.3 Mb Xp22.2 deletion identified in our kindred arose de novo in the proband's mother (on the grandfather's homolog), and produced extreme skewing of X‐inactivation via a “cell lethal” mechanism. We introduce a novel multitarget approach for X‐inactivation analysis using multiple informative differentially methylated SNPs, as an alternative to the classical single locus (HUMARA) method. We propose that for females with unexplained severe phenotypic expression of an X‐linked recessive disorder trio‐SNP microarray should be undertaken in combination with X‐inactivation analysis.

Dear Editor, Familial adenomatous polyposis is an autosomal dominant disorder caused by a germline mutation of the tumour suppressor gene adenomatous polyposis coli (APC) located on chromosome 5q22.2. Familial adenomatous polyposis is characterized by the development of hundreds of polyps in the colorectum, typically beginning in the second or third decade of life and eventually progressing to colorectal cancer in nearly all individuals if left untreated.

Background: It has been known for approximately 19 years that germline mutations in RUNX1, lead to familial platelet disorder with predisposition to myeloid malignancy (FPD-MM, OMIM 601399). Since that time researchers have identified a broad range of different RUNX1 mutations, in over 100 families. In large families, the diagnosis of malignancy shows variable penetrance among family members with the same mutation; some carriers of RUNX1 mutations do not develop malignancy. The causes of this heterogeneity are currently not known, complicating counselling and risk analysis for individual carriers. Recent advances in genetic sequencing technology applied by many FPD-MM research groups around the world have highlighted their value in understanding the somatic genetic changes that are associated with development of malignancies in germline RUNX1 mutation carriers. Collectively this information could lead to powerful insights essential for more precise risk assessment, monitoring, and therapeutic intervention. Specifically, a growing catalogue of somatic mutations associated with germline RUNX1 malignancy offers the opportunity for informed monitoring of asymptomatic RUNX1 carriers for additional high-risk somatic mutations, in turn providing the possibility for early therapeutic intervention to arrest the leukemic process. The challenge in advancing these goals for FPD-MM is the relative rarity of the disorder in individual populations. Global data sharing in a highly interactive FPD-MM research community offers a solution to this problem that benefits all patients world-wide. Aims: To create a global RUNX1 network through identifying and contacting researchers and clinicians with known and novel germline RUNX1 families, seeking their collaboration to share genomics data. To create a RUNX1.db portal to collectively house and analyse genomics data from germline RUNX1 carriers, with associated phenotype and clinical information, such that researchers have an ongoing means by which to combine their data with those generated by other groups around the world. Methods: RUNX1 network : Through existing collaborative networks, a systematic review of the literature, and referrals from initial contacts, we have identified a global network of researchers managing FPD-MM cases and families. RUNX1.db: We have adapted a custom-built variant analysis platform, VariantGrid, that is a visual web application and database designed to help scientists manage and analyse DNA variants that can be used to aggregate and analyse multiple datasets. Results: Preliminary analysis of aggregated data from the literature suggests there are features of germline RUNX1 syndrome that can be ascertained. These include frequent somatic mutation of RUNX1 in malignancy development, as well as mutations in genes associated with clonal hematopoiesis that may precede development of overt leukemia. This analysis also suggests that different types of germline RUNX1 mutations may be associated with different combinations of somatic mutations in the tumour. To further this analysis, we have identified over 70 groups internationally that either manage RUNX1 families or have identified potential germline carriers through genomics initiatives. This represents a large and growing resource for both scientific studies and clinical programs to benefit individuals with FPD-MM. Many of these groups have generated NGS data sets from patient samples which will be available for analysis through this portal. Further details and activities of the network, and results from the genomics aggregation database will be presented. Conclusion: We have created a global RUNX1 network, aggregated their data, and generated a RUNX1.db genomics portal for the continuous curation of genomics data from germline RUNX1 carriers. A preliminary analysis has already identified specific features of germline RUNX1 mutated malignancies that have clinical importance. Ongoing scientific and clinical studies through the RUNX1 network will enhance the power of aggregated data analysis, with RUNX1.db providing a central link, driving new insights that benefit patients. Disclosures Natsoulis: Imago BioSciences, Inc.: Consultancy, Equity Ownership. Guzman:Cellectis: Research Funding. DiNardo:Bayer: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Agios: Consultancy; Medimmune: Honoraria; Abbvie: Honoraria. Borate:Novartis: Consultancy; Agios: Consultancy. Wei:Amgen: Honoraria, Other: Advisory committee, Research Funding; Pfizer: Honoraria, Other: Advisory committee; Celgene: Honoraria, Other: Advisory committee, Research Funding; Abbvie: Honoraria, Other: Advisory board, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Other: Advisory committee, Research Funding; Novartis: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau. Dokal:MRC, Bloodwise, Telomerase Activator Sciences: Research Funding; The Gary Woodward Dyskeratosis Congenita Trust: Membership on an entity's Board of Directors or advisory committees; Action Medical Research, European School of Haematology: Membership on an entity's Board of Directors or advisory committees; Barts and The London School of Medicine and Dentistry, Queen Mary University of London,: Employment, Research Funding; Telomerase Activator Sciences: Research Funding; Barts and The London, Queen Mary University of London: Employment; Gary Woodward Dyskeratois Congenita Trust: Membership on an entity's Board of Directors or advisory committees. Hiwase:Novartis: Research Funding; Celgene: Research Funding. Branford:Cepheid: Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kramer:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Daiichi Sankyo: Consultancy. Owen:Merck: Honoraria; Teva: Honoraria; AbbVie: Research Funding; Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Research Funding; AstraZeneca: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding. Fitzgibbon:Epizyme: Consultancy, Research Funding; Gilead: Consultancy. Rienhoff:Imago BioSciences, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Kurokawa:Astellas Pharma: Research Funding; Sumitomo Dainippon Pharma: Research Funding; Nippon Sinyaku: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Eizai: Research Funding; MSD: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Pfizer: Research Funding; Takeda Pharmaceutical: Research Funding; Otsuka Pharmaceutical: Research Funding; Teijin Pharma: Research Funding; Chugai Pharmaceutical: Research Funding.

Contains fulltext : 71384.pdf (Publisher’s version ) (Closed access) We present prenatal and postnatal features of a patient with severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN). Mutation analysis confirmed the clinical diagnosis by detecting the FGFR3 Lys650Met mutation. This case, one of only six with molecular analysis reported in the literature, confirms the severe morbidity and adds to the reports with early mortality associated with SADDAN. Clinical-radiological characteristics of all reported cases of SADDAN are reviewed and discussed.

Background: This year, germline predisposition to haematological malignancy (HM) debuts in the World Health Organization classification of myeloid neoplasms and acute leukemia (Blood, 2016;127:2391). It has been 17 years since germline mutations in RUNX1 were found to lead to familial platelet disorder (FPD) with predisposition to myelodysplastic syndrome and acute myeloid leukaemia (MDS/AML) (Nat Genet. 1999;23:166). Now, nearly 80 families have been reported with damaging germline mutations or deletions affecting RUNX1 function, associated with FPD, making it an increasingly significant clinical presence. Although thrombocytopenia and platelet dysfunction are present in almost all RUNX1 mutant carriers, we and others have observed that the predisposition to HM varies between family members, with respect to age at diagnosis and the type of malignancy, and in some cases RUNX1 mutation carriers have no apparent HM development over their lifespan. The reasons for this heterogeneity are currently unknown. Aims: We are conducting an international collaborative study examining RUNX1 mutated families. The aim of the research project is to classify the range of phenotypes correlated with RUNX1 mutations comprehensively (including non-malignant phenotypes such as skin disorders) and to determine if the type of RUNX1 mutation and the presence of other germline and acquired mutations in relevant HM genes correlate with the likelihood of HM development, or the type of HM that develops. Across all of our data we aim to analyse clinically relevant information that will be used to inform prognosis and clinical management in germline RUNX1 mutation carriers. Results:From a review of the literature for previously characterised RUNX1 mutant families most mutations are predicted to be loss-of-function, with the combination of frameshift, stopgain, splicing and deletion accounting for the majority of alterations (57, 70%) compared to missense mutations (22, Figure 1). The most common sites of mutation are R201 and R204, affected by both missense and stopgain (10 total), which lie within the nuclear localisation signal at the end of the RUNT domain (Figure 1). We also surveyed in detail 12 RUNX1 pedigrees with both novel and previously described missense, frameshift, stopgain and deletion mutations and found that, while all families developed myeloid malignancies, 6 families also had individuals who developed lymphoid malignancy (most often Acute lymphoblastic leukemia (ALL)) which was heritable in sub-families, and subject to anticipation (e.g see IV-5 and V-5 in Figure 2). Consistent with population genome wide association studies identifying RUNX1 as a susceptibility locus for psoriasis (J Autoimmun. 2015;64:66), we find that skin conditions (psoriasis, eczema) are common, and present in germline RUNX1 carriers in 50% of our families; most commonly observed in families with stopgain and frameshift mutations. Genomic analysis of selected samples confirms that mutation of the other RUNX1 allele is the most commonly acquired mutation in germline RUNX1 mutation carriers developing HM. Alterations of chromosomes 21 and 7 are also common. DNMT3A and PHF6 acquired mutations were the next most frequently observed in tumors and mutations in U2AF1 and ASXL1 in the blood of RUNX1 carriers without HM were observed, suggestive of pre-HM clonal expansion. Finally, in a family with a novel R169I RUNX1 mutation, a rare germline ASXL1 variant (E1102D, 1.0% in ExAC) was found in two RUNX1 carriers who developed early onset AML. This variant is also significantly enriched in an MDS cohort unselected for family history compared to the general population (HR 1.3, p=0.02), as well as ASXL1 N986S (0.1% in ExAC, HR 3.3, p=0.0002) suggesting they operate as germline HM risk modifiers. Interestingly RUNX1 and ASXL1 acquired mutations often co-occur in sporadic MDS/AML and our data suggests this collaboration may also occur at the germline level. Conclusions:Annotation of skin phenotypes co-existent with a family history of haematological malignancy may assist in identifying RUNX1 mutant families. Both acquired and germline mutations in known HM genes may modify germline RUNX1 driven HM penetrance and phenotype. Our data suggest that screening of RUNX1 germline mutation carriers for germline and acquired variants in other HM genes could provide an important tool for defining risk and requires further investigation. Disclosures Owen: Pharmacyclics: Research Funding; Janssen: Honoraria; Roche: Honoraria, Research Funding; Novartis: Honoraria; Gilead: Honoraria, Research Funding; Lundbeck: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria. Godley:UpToDate: Honoraria; Onconova, Inc.: Research Funding.

Anophthalmia (no eye), microphthalmia (small eye) and associated ocular developmental anomalies cause significant visual handicap. In most cases the underlying genetic cause is unknown, but mutations in some genes, such as SOX2, cause ocular developmental defects, particularly anophthalmia, in a subset of patients. Here, we describe a four-generation family with a p.Asp123Gly mutation in the highly conserved partner-factor interaction region of the SOX2 protein, which is important for cell-specific actions of SOX2. The proband in this family has bilateral anophthalmia and several other family members have milder ocular phenotypes, including typical optic fissure coloboma. Expression studies indicate that Sox2 is expressed in the eye at the site of closure of the optic fissure during development. The SOX2 mutation in this family implicates the partner-factor interaction region of SOX2 in contributing to the specificity of SOX2 action in optic fissure closure. Our findings indicate that investigation of SOX2 in a broad range of eye anomaly patients aids in the determination of particular functions of SOX2 in development.

We present a case of Beare-Stevenson syndrome with a broad range of phenotypic features including craniosynostosis, cutis gyrata, choanal stenosis, bifid scrotum with perineal hypospadias and a caudal appendage. The paternal age at the time of conception was 62 years consistent with a paternal age effect. Mutation analysis was undertaken and demonstrated the FGFR2 Y375C mutation. This case, one of only nine with molecular analysis, confirms the significant morbidity associated with this syndrome.