Risk assessment and genetic counseling for Lynch syndrome – Practice resource of the National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer

Holter, Spring; Hall, Michael J.; Hampel, Heather; Jasperson, Kory; Kupfer, Sonia S.; Haidle, Joy Larsen; Mork, Maureen E.; Palaniapppan, Selvi; Senter, Leigha; Stoffel, Elena M.; Weissman, Scott M.; Yurgelun, Matthew B.

doi:10.1002/jgc4.1546

Cited by 11 publications

(11 citation statements)

References 127 publications

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“…Lynch syndrome is the most common hereditary CRC syndrome and accounts for ∼2% to 4% of all CRC (American Cancer Society, 2020) and 3% of endometrial cancer (Holter et al., 2022; Weissman et al., 2011). Lynch syndrome is caused by pathogenic variants in the mismatch repair genes, MLH1 , MSH2 , MSH6 , and PMS2 .…”

Section: Commentarymentioning

confidence: 99%

Hereditary Colorectal Cancer Diagnosis by Next‐Generation Sequencing

Wen,

Ehivet,

Stanislaw

et al. 2023

Current Protocols

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Pathogenic germline variants causally contribute to the etiology of colorectal cancer (CRC) and polyposis. The era of massively parallel sequencing, also known as next‐generation sequencing (NGS), make it highly possible, effective, and efficient to offer rapid and cost‐effective diagnosis for CRC. To aid clinical laboratories in testing the most clinically significant genes, along with the published ACMG CRC technical standard guidelines, this protocol aims to provide a step‐by‐step technical workflow for carrying out the NGS‐panel based CRC molecular diagnosis focusing on the wet lab portion of library preparation and massively parallel sequencing. Using the most popular pull‐down‐based target enrichment, the chapter particularly encompasses genomic DNA (gDNA) fragmentation, adapter ligation, indexing, hybridization, and capture, which is the most variable and technically challenging part of NGS testing involving at least 3 quality control (QC) checkpoints plus the pre‐ and post‐capture PCR. The gDNA extraction and sequencing is less covered because they are relatively standard technologies with little variations and choices. Although this protocol also introduces pertinent testing algorithms and a brief guideline for pre‐ and post‐testing genetic counselling, the audiences are required to refer to National Comprehensive Cancer Network (NCCN) clinical practice guidelines to determine the most appropriate testing strategies. Since NGS panel‐based testing is a highly complex and dynamic platform with multiple choices from different technology and commercial resources, this technical benchtop‐based protocol also aims to cover some of the key ramification points for decision‐making by each laboratory at the discretion of the directors. © 2023 Wiley Periodicals LLC.Basic Protocol: Hereditary colorectal cancer (CRC) diagnosis by next‐generation sequencing

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Section: Commentarymentioning

confidence: 99%

Hereditary Colorectal Cancer Diagnosis by Next‐Generation Sequencing

Wen,

Ehivet,

Stanislaw

et al. 2023

Current Protocols

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“…Current guidelines from the National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer state that the term Lynch syndrome should only be used for individuals identified as having germline heterozygous pathogenic variants in MLH1, MSH2, MSH6, PMS2, and EPCAM to prevent confusion. 14 Although this family actually did have Lynch syndrome, at the time the note was written there was no review or proof that the family had a pathogenic variant. When the term is not correctly used, assumptions about risk and prior testing are made that may or may not be correct.…”

Section: Terminology Mattersmentioning

confidence: 99%

Laboratory Selection in Germline Genetic Testing: Laboratory Science Matters

Mahon

2023

Journal of the National Comprehensive Cancer Network

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There are multiple laboratories that offer germline genetic testing, and it can be difficult to discern which one to use for testing. Some laboratories have more comprehensive analysis techniques and capability, which increases the accuracy of testing. The ordering provider has a responsibility to select the appropriate laboratory with technologic capability for the needed testing, inform the laboratory of prior testing results in the patient and family so known familial variants have targeted testing, and use appropriate terminology and nomenclature when communicating information to other healthcare professionals, patients, and families. This report presents a case illustrating the potential errors that can occur when a provider selects a laboratory that lacks the capacity to detect certain pathogenic variants, such as large deletions and duplications. False-negative germline testing results lead to missed opportunities in prevention and early detection for not only the patient but often multiple family members, which may lead to psychosocial distress and late-detected cancers. This case highlights the complexities of genetic care and why management by a genetics professional can facilitate more fiscally responsible care, appropriate genetic testing, and comprehensive care for all family members at risk.

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“…101 A recent statement from the ACMG addresses the management of PALB2 heterozygotes. 13 Clinical practice guidelines and recommendations exist for the management of Lynch syndrome, 33,37,103,236,237 as well as polyposis syndromes. neurofibromatosis type 1, 243,244 Li-Fraumeni syndrome, 245 von Hippel-Lindau disease, 246 multiple endocrine neoplasia type 1, 247 basal cell carcinomas in Gorlin syndrome, 248 pheochromocytoma and paraganglioma, 249,250 SDHA pathogenic germline variant carriers, 109 and DICER1 tumor predisposition.…”

Section: Gene-disease Relationships Penetrance and Inclusion On Hered...mentioning

confidence: 99%

“…Deletions in the 3′ region of EPCAM which result in silencing of downstream MSH2 through hyper‐rmethylation 29–31 …”

Section: Hereditary Cancer Syndrome Genesmentioning

confidence: 99%

Principles of molecular testing for hereditary cancer

Mighton

Lerner‐Ellis

2022

Genes Chromosomes & Cancer

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Molecular testing for hereditary cancers has rapidly advanced over the past two decades. Next-generation sequencing has been widely adopted, which has made molecular testing increasingly accessible, and large gene panels are now routinely used in clinical care. Effectively using molecular testing as a tool for the management of patients with hereditary cancer involves understanding various basic principles. In this article, we provide an overview of general principles for molecular germline testing for hereditary cancer syndromes. We overview hereditary cancer etiology, clinical indications for molecular testing, test methodologies and limitations, interpretation and reporting of test results, the evolving nature of evidence on gene-disease relationships and penetrance, and resources related to the clinical management of hereditary cancer syndromes.

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Risk assessment and genetic counseling for Lynch syndrome – Practice resource of the National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer

Cited by 11 publications

References 127 publications

Hereditary Colorectal Cancer Diagnosis by Next‐Generation Sequencing

Hereditary Colorectal Cancer Diagnosis by Next‐Generation Sequencing

Laboratory Selection in Germline Genetic Testing: Laboratory Science Matters

Principles of molecular testing for hereditary cancer

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