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Diagnostic yield of a custom-designed multi-gene cancer panel in Irish patients with breast cancer

Abstract

Background

Breast cancer is genetically heterogeneous, and parellel multi-gene sequencing is the most cost- and time-efficient manner to investigate breast cancer predisposition. Numerous multi-gene panels (MGPs) are commercially available, but many include genes with weak/unproven associaton with breast cancer, or with predisposition to cancer of other types. This study investigates the utility of a custom-designed multi-gene panel in an Irish cohort with breast cancer.

Methods

A custom panel comprising 83 genes offered by 19 clinical “breast cancer predisposition” MGPs was designed and applied to germline DNA from 91 patients with breast cancer and 77 unaffected ethnicially matched controls. Variants were identified and classified using a custom pipeline.

Results

Nineteen loss-of-function (LOF) and 334 missense variants were identified. After removing common and/or benign variants, 15 LOF and 30 missense variants were analysed. Variants in known breast cancer susceptibility genes were identified, including in BRCA1 and ATM in cases, and in NF1 and CHEK2 in controls. Most variants identified were in genes associated with predisposition to cancers other than breast cancer (BRIP1, RAD50, MUTYH, and mismatch repair genes), or in genes with unknown or unproven association with cancer.

Conclusion

Using multi-gene panels enables rapid, cost-effective identification of individuals with high-risk cancer predisposition syndromes. However, this approach also leads to an increased amount of uncertain results. Clinical management of individuals with particular genetic variants in the absence of a matching phenotype/family history is challenging. Further population and functional evidence is required to fully elucidate the clinical relevance of variants in genes of uncertain significance.

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Change history

  • 18 February 2020

    The originally published version of this article contained typesetting errors in Figs. 2 and 3 legends. The correct figure legends are presented here. The original article has been corrected.

Abbreviations

MAF:

Minor allele frequency

NFE:

Non-Finnish European

GWAS:

Genome-wide assocation study

NGS:

Next-generation sequencing

MGP:

Multi-gene panel

VUS:

Variant of uncertain significance

GATK:

Genome Analysis Toolkit

LOF:

Loss-of-function

SNP:

Single nucleotide polymorphism

PCA:

Principle component analysis

VUS:

Variant(s) of uncertain significance

CRC:

Colorectal cancer

LS:

Lynch syndrome

LD:

Linkage disequilibrium

GUS:

Gene(s) of uncertain significance

InSiGHT:

The International Society for Gastrointestinal Hereditary Tumours

ENIGMA:

Evidence-based Network for the Interpretation of Germline Mutant Alleles

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Funding

This study was supported and funded with thanks by the National Breast Cancer Research Institute (NBCRI), the Health Service Executive/Health Research Board National Specialist Academic Fellowship (NSAFP 2014/1), and the Monkstown Hospital Foundation.

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Correspondence to Úna M. McVeigh.

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The original version of this article was revised: The originally published version of this article contained typesetting errors in Figure 2 and 3 legends. This has been corrected.

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McVeigh, Ú.M., McVeigh, T.P., Curran, C. et al. Diagnostic yield of a custom-designed multi-gene cancer panel in Irish patients with breast cancer. Ir J Med Sci (2020). https://doi.org/10.1007/s11845-020-02174-x

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Keywords

  • Familial breast cancer
  • Multi-gene panel
  • Next-generation sequencing