DNA breakpoint assay reveals a majority of gross duplications occur in tandem reducing VUS classifications in breast cancer predisposition genes

Richardson, Marcy E.; Chong, Hansook Kim; Mu, Wenbo; Conner, Blair R.; Hsuan, Vickie; Willett, Sara; Lam, Stephanie; Tsai, Pei Ching; Pesaran, Tina; Chamberlin, Adam C.; Park, Minsun; Gray, Phillip; Karam, Rachid; Elliott, Aaron

doi:10.1038/s41436-018-0092-7

Cited by 20 publications

(22 citation statements)

References 39 publications

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“…13 This finding was confirmed by another study of breast cancer genes showing that duplications occurred in tandem 78% of the time with unknown status for the remainder. 14 In contrast to tandem duplications involving an entire gene or either end of the gene, tandem intragenic duplications are likely to alter the gene product. For most genes, using PM4 for duplications not involving the 5' and/or 3' end (presumed intragenic) is recommended if consistent with the mechanism of disease.…”

Section: Pm4mentioning

confidence: 99%

Adapting ACMG/AMP sequence variant classification guidelines for single-gene copy number variants

Brandt¹,

Sack²,

Arjona³

et al. 2020

Genetics in Medicine

107

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The ability of a single technology, next-generation sequencing, to provide both sequence and copy number variant (CNV) results has driven the merger of clinical cytogenetics and molecular genetics. Consequently, the distinction between the definition of a sequence variant and a CNV is blurry. As the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards and guidelines for interpretation of sequence variants address CNV classification only sparingly, this study focused on adapting ACMG/AMP criteria for single-gene CNV interpretation.Methods: CNV-specific modifications of the 2015 ACMG/AMP criteria were developed and their utility was independently tested by three diagnostic laboratories. Each laboratory team interpreted the same 12 single-gene CNVs using three systems: (1) without ACMG/AMP guidance, (2) with ACMG/AMP criteria, and (3) with new modifications. A replication study of 12 different CNVs validated the modified criteria.Results: The adapted criteria system presented here showed improved concordance and usability for single-gene CNVs compared with using the ACMG/AMP interpretation guidelines focused on sequence variants. Conclusion:These single-gene CNV criteria modifications could be used as a supplement to the ACMG/AMP guidelines for sequence variants, allowing for a streamlined workflow and a step toward a uniform classification system for both sequence and copy number alterations.

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Section: Pm4mentioning

confidence: 99%

Adapting ACMG/AMP sequence variant classification guidelines for single-gene copy number variants

Brandt¹,

Sack²,

Arjona³

et al. 2020

Genetics in Medicine

107

View full text Add to dashboard Cite

show abstract

“…Although one cannot assume duplications are in tandem, current data suggest that at least 83% of duplications (including exon level) are in tandem (Newman, Hermetz, Weckselblatt, & Rudd, ; Richardson et al ). Consequently, a duplication at an unknown insertion site is only downgraded one step to PVS1_Strong strength level provided it is predicted to shift the reading frame and cause NMD (Figure ).…”

Section: Resultsmentioning

confidence: 99%

Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion

et al. 2018

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The 2015 ACMG/AMP sequence variant interpretation guideline provided a framework for classifying variants based on several benign and pathogenic evidence criteria, including a pathogenic criterion (PVS1) for predicted loss of function variants. However, the guideline did not elaborate on specific considerations for the different types of loss of function variants, nor did it provide decision-making pathways assimilating information about variant type, its location, or any additional evidence for the likelihood of a true null effect. Furthermore, this guideline did not take into account the relative strengths for each evidence type and the final outcome of their combinations with respect to PVS1 strength. Finally, criteria specifying the genes for which PVS1 can be applied are still missing. Here, as part of the ClinGen Sequence Variant Interpretation (SVI) Workgroup's goal of refining ACMG/AMP criteria, we provide recommendations for applying the PVS1 criterion using detailed guidance addressing the above-mentioned gaps. Evaluation of the refined criterion by seven disease-specific groups using heterogeneous types of loss of function variants (n = 56) showed 89% agreement with the new recommendation, while discrepancies in six variants (11%) were appropriately due to disease-specific refinements. Our recommendations will facilitate consistent and accurate interpretation of predicted loss of function variants.

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“…Other type of alterations that do not elicit NMD and may not result in LoF include in-frame exon duplications proven to be in tandem (Richardson et al, 2018) and exon deletions located in exons that are in-frame: exon 4 (144 nt. ), exon 5 (156 nt.…”

Section: Resultsmentioning

confidence: 99%

Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline CDH1 sequence variants

Lee

Krempely

Roberts³

et al. 2018

Human Mutation

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155

154

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The variant curation guidelines published in 2015 by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) provided the genetics community with a framework to assess variant pathogenicity; however, these rules are not gene-specific. Germline pathogenic variants in the CDH1 gene cause hereditary diffuse gastric cancer and lobular breast cancer, a clinically challenging cancer predisposition syndrome that often requires a multidisciplinary team of experts to be properly managed. Given this challenge, the Clinical Genome Resource (ClinGen) Hereditary Cancer Domain prioritized the development of the CDH1 Variant Curation Expert Panel (VCEP) to develop and implement rules for CDH1 variant classifications. Here we describe the CDH1 specifications of the ACMG/AMP guidelines, which were developed and validated after a systematic evaluation of variants obtained from a cohort of clinical laboratory data encompassing ~827,000 CDH1 sequenced alleles. Comparing previously reported germline variants that were classified using the 2015 ACMG/AMP guidelines to the CDH1 VCEP recommendations resulted in reduced variants of uncertain significance and facilitated resolution of variants with conflicted assertions in ClinVar. Overall, the ClinGen CDH1 VCEP recommends the use of these CDH1-specific guidelines for the assessment and classification of variants identified in this clinically actionable gene.

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DNA breakpoint assay reveals a majority of gross duplications occur in tandem reducing VUS classifications in breast cancer predisposition genes

Cited by 20 publications

References 39 publications

Adapting ACMG/AMP sequence variant classification guidelines for single-gene copy number variants

Adapting ACMG/AMP sequence variant classification guidelines for single-gene copy number variants

Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion

Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline CDH1 sequence variants

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