scholarly journals Multilocus Inherited Neoplasia Allele Syndrome (MINAS): an update

2022 ◽  
Author(s):  
Anthony McGuigan ◽  
James Whitworth ◽  
Avgi Andreou ◽  
Timothy Hearn ◽  
J. C. Ambrose ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Cancer Susceptibility ◽  
Clinical Phenotype ◽  
Pathogenic Variants ◽  
Complex Interactions ◽  
Cancer Susceptibility Genes ◽  
Multiple Primary ◽  
Brca1 Brca2 ◽  
The Uk ◽  
Multiple Tumour

AbstractMulti-locus Inherited Neoplasia Allele Syndrome (MINAS) refers to individuals with germline pathogenic variants in two or more cancer susceptibility genes(CSGs). With increased use of exome/genome sequencing it would be predicted that detection of MINAS would become more frequent. Here we review recent progress in knowledge of MINAS. A systematic literature search for reports of individuals with germline pathogenic variants in 2 or more of 94 CSGs was performed. In addition, participants with multiple primary tumours who underwent genome sequencing as part of the Rare Disease arm of the UK 100,000 Genomes Project were interrogated to detect additional cases. We identified 385 MINAS cases (211 reported in the last 5 years, 6 from 100,000 genomes participants). Most (287/385) cases contained at least one pathogenic variant in either BRCA1 or BRCA2. 108/385 MINAS cases had multiple primary tumours at presentation and a subset of cases presented unusual multiple tumour phenotypes. We conclude that, as predicted, increasing numbers of individuals with MINAS are being have been reported but, except for individuals with BRCA1/BRCA2 MINAS, individual CSG combinations are generally rare. In many cases it appears that the clinical phenotype is that which would be expected from the effects of the constituent CSG variants acting independently. However, in some instances the presence of unusual tumour phenotypes and/or multiple primary tumours suggests that there may be complex interactions between the relevant MINAS CSGs. Systematic reporting of MINAS cases in a MINAS database (e.g. https://databases.lovd.nl/shared/diseases/04296) will facilitate more accurate prognostic predictions for specific CSG combinations.

Management of germline findings revealed throughout the course of tumor-normal whole genome sequencing in oncology.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13113-e13113
Author(s):  
Howard John Lim ◽  
Kasmintan A Schrader ◽  
Sean Young ◽  
Jessica Nelson ◽  
Alexandra Fok ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Susceptibility Genes ◽  
Genomic Research ◽  
Whole Genome ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes

e13113 Background: The Personalized OncoGenomics (POG) project at the BC Cancer Agency utilizes tumor-normal whole genome sequencing (WGS) to understand key driver pathways and guide personalized treatment decisions. Analysis of the germline data can reveal variants; these may be presumed pathogenic, presumed benign or of unknown significance (VUS). We have developed a process for evaluating and returning presumed pathogenic variants in known cancer susceptibility genes to patients, for counseling and validation in a clinical-accredited laboratory. Methods: Patients receive germline cancer related information as part of the consent process for participation in the POG program. A sub-committee comprised of medical geneticists, bioinformaticians, pathologists, oncologists and an ethicist review the germline results. Any variants suspicious of being an artifact undergo a technical validation step. Presumed pathogenic findings of known cancer susceptibility genes are returned to the patient by their treating oncologist and patients are referred to the Hereditary Cancer Program (HCP), for genetic counseling and clinical confirmation. Results: From June 2012 - January 2017 – 466 patients have consented to the project. To date, 39 cases (8.4%) had at least one variant that was deemed pathogenic, 86 cases had at least one VUS in a known cancer susceptibility gene. 11 out of 23 cases (47.8%) with high penetrance mutations were already known to HCP. All VUS were reviewed by the sub-committee taking in to consideration the VUS and clinical context. 8 of the subjects with pathogenic results and 3 with VUS were known to HCP before POG data was generated. A VUS in 7 cases (1.5%) was returned after review. Conclusions: The number of pathogenic variants in known cancer susceptibility genes is consistent with published oncology results. We created a process to manage clinically relevant germline findings discovered during the course of genomic research to ensure appropriate care for patients. Genetic counseling within HCP and validation of variants in the clinically accredited Cancer Genetics Laboratory enables seamless return of research generated clinically relevant germline results to affected subjects. Clinical trial information: NCT02155621.

scholarly journals Penetrance of breast cancer genes from the eMERGE III Network

2021 ◽  
Author(s):  
Xiao Fan ◽  
Julia Wynn ◽  
Shang Ning ◽  
Cong Liu ◽  
Alexander Fedotov ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Population Based ◽  
Cancer Genes ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Potential Clinical Impact ◽  
Brca1 Brca2 ◽  
Genetic Results

We studied the penetrance and clinical outcomes of seven breast cancer susceptibility genes (BRCA1, BRCA2, TP53, CHEK2, ATM, PALB2 and PTEN) in almost 25,000 participants unselected for personal or family history of breast cancer. We identified 420 participants with pathogenic or likely pathogenic variants, and 147 were women who did not previously know their genetic results. Out of these 147 women, 32 women were diagnosed with breast cancer at an average age of 52.8 years. Estimated penetrance by age 60 years ranged from 18-44%, depending on the gene. Within the first twelve months after genetic results disclosure, 42% of women had taken actions related to their genetic results and two new breast cancer cases were identified. Our study provides population-based penetrance estimates for the understudied genes, CHEK2, ATM, and PALB2, and highlights the importance of using unselected populations for penetrance studies. It also demonstrates the potential clinical impact of genetic testing to improve healthcare through early diagnosis and preventative screening.

scholarly journals Prevalence of Pathogenic Variants in Cancer Susceptibility Genes Among Women With Postmenopausal Breast Cancer

JAMA ◽  
2020 ◽  
Vol 323 (10) ◽  
pp. 995 ◽  
Author(s):  
Allison W. Kurian ◽  
Ryan Bernhisel ◽  
Katie Larson ◽  
Jennifer L. Caswell-Jin ◽  
Aladdin H. Shadyab ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Postmenopausal Breast Cancer ◽  
Susceptibility Genes ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes

scholarly journals Cancer Variant Interpretation Group UK (CanVIG-UK): an exemplar national subspecialty multidisciplinary network

2020 ◽  
Vol 57 (12) ◽  
pp. 829-834 ◽  
Author(s):  
Alice Garrett ◽  
Alison Callaway ◽  
Miranda Durkie ◽  
Cankut Cubuk ◽  
Mary Alikian ◽  
...  
Keyword(s):  
Cancer Susceptibility ◽  
Genomic Medicine ◽  
Genomic Analysis ◽  
Variant Interpretation ◽  
General Acceptance ◽  
Online Portal ◽  
Cancer Susceptibility Genes ◽  
Multidisciplinary Meetings ◽  
Medicine Service ◽  
The Uk

Advances in technology have led to a massive expansion in the capacity for genomic analysis, with a commensurate fall in costs. The clinical indications for genomic testing have evolved markedly; the volume of clinical sequencing has increased dramatically; and the range of clinical professionals involved in the process has broadened. There is general acceptance that our early dichotomous paradigms of variants being pathogenic–high risk and benign–no risk are overly simplistic. There is increasing recognition that the clinical interpretation of genomic data requires significant expertise in disease–gene-variant associations specific to each disease area. Inaccurate interpretation can lead to clinical mismanagement, inconsistent information within families and misdirection of resources. It is for this reason that ‘national subspecialist multidisciplinary meetings’ (MDMs) for genomic interpretation have been articulated as key for the new NHS Genomic Medicine Service, of which Cancer Variant Interpretation Group UK (CanVIG-UK) is an early exemplar. CanVIG-UK was established in 2017 and now has >100 UK members, including at least one clinical diagnostic scientist and one clinical cancer geneticist from each of the 25 regional molecular genetics laboratories of the UK and Ireland. Through CanVIG-UK, we have established national consensus around variant interpretation for cancer susceptibility genes via monthly national teleconferenced MDMs and collaborative data sharing using a secure online portal. We describe here the activities of CanVIG-UK, including exemplar outputs and feedback from the membership.

scholarly journals Improved structural variant interpretation for hereditary cancer susceptibility using long-read sequencing

2020 ◽  
Vol 22 (11) ◽  
pp. 1892-1897 ◽  
Author(s):  
My Linh Thibodeau ◽  
Kieran O’Neill ◽  
Katherine Dixon ◽  
Caralyn Reisle ◽  
Karen L. Mungall ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Hereditary Cancer ◽  
Cancer Susceptibility ◽  
Return Of Results ◽  
Advanced Cancer Patients ◽  
Short Read ◽  
Cancer Susceptibility Genes ◽  
Oxford Nanopore ◽  
Long Read ◽  
Tumor Genome

Abstract Purpose Structural variants (SVs) may be an underestimated cause of hereditary cancer syndromes given the current limitations of short-read next-generation sequencing. Here we investigated the utility of long-read sequencing in resolving germline SVs in cancer susceptibility genes detected through short-read genome sequencing. Methods Known or suspected deleterious germline SVs were identified using Illumina genome sequencing across a cohort of 669 advanced cancer patients with paired tumor genome and transcriptome sequencing. Candidate SVs were subsequently assessed by Oxford Nanopore long-read sequencing. Results Nanopore sequencing confirmed eight simple pathogenic or likely pathogenic SVs, resolving three additional variants whose impact could not be fully elucidated through short-read sequencing. A recurrent sequencing artifact on chromosome 16p13 and one complex rearrangement on chromosome 5q35 were subsequently classified as likely benign, obviating the need for further clinical assessment. Variant configuration was further resolved in one case with a complex pathogenic rearrangement affecting TSC2. Conclusion Our findings demonstrate that long-read sequencing can improve the validation, resolution, and classification of germline SVs. This has important implications for return of results, cascade carrier testing, cancer screening, and prophylactic interventions.

Improving cascade genetic testing for families with inherited pancreatic cancer (PDAC) risk: The genetic education, risk assessment and testing (GENERATE) study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS4162-TPS4162
Author(s):  
Matthew B. Yurgelun ◽  
C. Sloane Furniss ◽  
Barbara Kenner ◽  
Alison Klein ◽  
Catherine C. Lafferty ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Cancer Susceptibility ◽  
Genetic Counselor ◽  
Cancer Worry ◽  
Genetic Education ◽  
Degree Relative ◽  
Cascade Testing ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Germline Testing

TPS4162 Background: 4-10% of PDAC patients harbor pathogenic germline variants in cancer susceptibility genes, including APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, and TP53. For families with such pathogenic variants, the greatest potential impact of germline testing is to identify relatives with the same pathogenic variant (cascade testing), thereby providing the opportunity for early detection and cancer interception of PDAC and other associated malignancies. Numerous factors limit cascade testing in real-world practice, including family dynamics, widespread geographic distribution of relatives, access to genetic services, and misconceptions about the importance of germline testing, such that the preventive benefits of cascade testing are often not fully realized. The primary aim of this study is to analyze two alternative strategies for cascade testing in families with inherited PDAC susceptibility. Methods: 1000 individuals (from approximately 200 families) with a confirmed pathogenic germline variant in any of the above genes in a 1st/2nd degree relative and a 1st/2nd degree relative with PDAC will be remotely enrolled through the study website (www.generatestudy.org) and randomized between two different methods of cascade testing (individuals with prior genetic testing will be ineligible): Arm 1 will undergo pre-test genetic education with a pre-recorded video and live interactive session with a genetic counselor via a web-based telemedicine platform (Doxy.me), followed by germline testing through Color Genomics; Arm 2 will undergo germline testing through Color Genomics without dedicated pre-test genetic education. Color Genomics will disclose results to study personnel and directly to participants in both arms. Participants in both arms will have the option of pursuing additional telephone-based genetic counseling through Color Genomics. The primary outcome will be uptake of cascade testing. Secondary outcomes will include participant self-reported genetic knowledge, cancer worry, distress, decisional preparedness, familial communication, and screening uptake, which will be measured via longitudinal surveys. Enrollment will begin February, 2019. Clinical trial information: NCT03762590.

scholarly journals Breast cancer risks associated with missense variants in breast cancer susceptibility genes

2021 ◽  
Author(s):  
Leila Dorling ◽  
Sara Carvalho ◽  
Jamie Allen ◽  
Michael Parsons ◽  
Cristina Fortuno ◽  
...  
Keyword(s):  
Breast Cancer ◽  
In Silico ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Cancer Risks ◽  
Functional Protein ◽  
Missense Variants ◽  
Cancer Susceptibility Genes ◽  
Gene Panel Testing ◽  
Brca1 Brca2

BACKGROUND Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2 and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. METHODS Combining 59,639 breast cancer cases and 53,165 controls, we sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1,146 training variants), BRCA1 (644), BRCA2 (1,425), CHEK2 (325) and PALB2 (472). We evaluated breast cancer risks according to five in-silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. RESULTS The most predictive in-silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1 and BRCA2, data were compatible with small subsets (approximately 7%, 2% and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. CONCLUSIONS These results will inform risk prediction models and the selection of candidate variants for functional assays, and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.

scholarly journals BRCA1/BRCA2 mutation spectrum analysis in South Asia: a systematic review

2022 ◽  
Vol 50 (1) ◽  
pp. 030006052110707
Author(s):  
Sanjeev Kharel ◽  
Suraj Shrestha ◽  
Siddhartha Yadav ◽  
Prafulla Shakya ◽  
Sujita Baidya ◽  
...  
Keyword(s):  
South Asian ◽  
Cancer Susceptibility ◽  
Brca2 Mutation ◽  
Brca2 Gene ◽  
Mutation Spectrum ◽  
Quality Data ◽  
Brca1 And Brca2 ◽  
Exon 2 ◽  
Cancer Susceptibility Genes ◽  
Brca1 Brca2

Objective Breast cancer (BC) is the most common form of cancer among Asian females. Mutations in the BRCA1/ BRCA2 genes are often observed in BC cases and largely increase the lifetime risk of having BC. Because of the paucity of high-quality data on the molecular spectrum of BRCA mutations in South Asian populations, we aimed to explore these mutations among South Asian countries. Methods A systematic literature search was performed for the BRCA1 and BRCA2 gene mutation spectrum using electronic databases such as PubMed, EMBASE, and Google Scholar. Twenty studies were selected based on specific inclusion and exclusion criteria. Results The 185delAG (c.68_69del) mutation in exon 2 of BRCA1 was the most common recurrent mutation and founder mutation found. Various intronic variants, variants of unknown significance, large genomic rearrangements, and polymorphisms were also described in some studies. Conclusions The South Asian population has a wide variety of genetic mutations of BRCA1 and BRCA2 that differ according to countries and ethnicities. A stronger knowledge of various population-specific mutations in these cancer susceptibility genes can help provide efficient strategies for genetic testing.

Sign in / Sign up

Export Citation Format

Share Document