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Familial Cancer

, Volume 12, Issue 4, pp 741–747 | Cite as

Multivariate analysis of MLH1 c.1664T>C (p.Leu555Pro) mismatch repair gene variant demonstrates its pathogenicity

  • M. P. Farrell
  • D. J. Hughes
  • M. Drost
  • A. J. Wallace
  • R. J. Cummins
  • T. A. Fletcher
  • M. A. Meany
  • E. W. Kay
  • N. de Wind
  • D. G. Power
  • E. J. Andrews
  • A. J. Green
  • D. J. Gallagher
Original Article

Abstract

Genetic testing of an Irish kindred identified an exonic nucleotide substitution c.1664T>C (p.Leu555Pro) in the MLH1 mismatch repair (MMR) gene. This previously unreported variant is classified as a “variant of uncertain significance” (VUS). Immunohistochemical (IHC) analysis and microsatellite instability (MSI) studies, genetic testing, a literature and online MMR mutation database review, in silico phenotype prediction tools, and an in vitro MMR activity assay were used to study the clinical significance of this variant. The MLH1 c.1664T>C (p.Leu555Pro) VUS co-segregated with three cases of classic Lynch syndrome-associated malignancies over two generations, with consistent loss of MLH1 and PMS2 protein expression on IHC, and evidence of the MSI-High mutator phenotype. The leucine at position 555 is well conserved across a number of species, and this novel variant has not been reported as a normal polymorphism in the general population. In silico and in vitro analyses suggest that this variant may have a deleterious effect on the MLH1 protein and abrogate MMR activity. Evidence from clinical, histological, immunohistochemical, and molecular genetic data suggests that MLH1 c.1664T>C (p.Leu555Pro) is likely to be the pathogenic cause of Lynch syndrome in this family.

Keywords

DNA mismatch repair (MMR) Immunohistochemistry (IHC) Lynch syndrome Microsatellite instability (MSI) MutL homolog 1 (MLH1Variant of uncertain significance (VUS) 

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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • M. P. Farrell
    • 1
  • D. J. Hughes
    • 2
  • M. Drost
    • 3
  • A. J. Wallace
    • 4
  • R. J. Cummins
    • 5
  • T. A. Fletcher
    • 4
  • M. A. Meany
    • 6
  • E. W. Kay
    • 5
  • N. de Wind
    • 3
  • D. G. Power
    • 8
  • E. J. Andrews
    • 8
  • A. J. Green
    • 6
    • 7
  • D. J. Gallagher
    • 1
    • 9
  1. 1.Cancer Genetics DepartmentMater Private HospitalDublin 7Ireland
  2. 2.Centre for Systems Medicine, Department of Physiology and Medical PhysicsRoyal College of Surgeons in IrelandDublin 2Ireland
  3. 3.Department of ToxicogeneticsLeiden University Medical CenterLeidenThe Netherlands
  4. 4.Regional Molecular Genetics ServiceManchester Academic Health Science CentreManchesterUK
  5. 5.Pathology DepartmentBeaumont HospitalDublin 9Ireland
  6. 6.The National Centre for Medical GeneticsOur Lady’s Children’s HospitalDublin 12Ireland
  7. 7.UCD School of Medicine and Medical ScienceDublinIreland
  8. 8.Cork University HospitalWilton, CorkIreland
  9. 9.Department of Cancer GeneticsSt. James’s HospitalDublin 8Ireland

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