A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants

TY - JOUR

T1 - A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants

AU - Drost, Mark

AU - Zonneveld, José B M

AU - van Hees, Sandrine

AU - Rasmussen, Lene Juel

AU - Hofstra, Robert M W

AU - de Wind, Niels

N1 - © 2011 Wiley Periodicals, Inc.

PY - 2012/3

Y1 - 2012/3

N2 - Lynch syndrome (LS) is an autosomal dominant disorder that predisposes to colon, endometrial, and other cancers. LS is caused by a heterozygous germline mutation in one of the DNA mismatch repair (MMR) genes. A significant proportion of all mutations found in suspected LS patients comprises single amino acid alterations. The pathogenicity of these variants of uncertain significance (VUS) is difficult to assess, precluding diagnosis of carriers and their relatives. Here we present a rapid cell-free assay to investigate MMR activity of MSH2 or MSH6 VUS. We used this assay to analyze a series of MSH2 and MSH6 VUS, selected from the Leiden Open Variation Database. Whereas a significant fraction of the MSH2 VUS has lost MMR activity, suggesting pathogenicity, the large majority of the MSH6 VUS appears MMR proficient. We anticipate that this assay will be an important tool in the development of a comprehensive and widely applicable diagnostic procedure for LS-associated VUS.

AB - Lynch syndrome (LS) is an autosomal dominant disorder that predisposes to colon, endometrial, and other cancers. LS is caused by a heterozygous germline mutation in one of the DNA mismatch repair (MMR) genes. A significant proportion of all mutations found in suspected LS patients comprises single amino acid alterations. The pathogenicity of these variants of uncertain significance (VUS) is difficult to assess, precluding diagnosis of carriers and their relatives. Here we present a rapid cell-free assay to investigate MMR activity of MSH2 or MSH6 VUS. We used this assay to analyze a series of MSH2 and MSH6 VUS, selected from the Leiden Open Variation Database. Whereas a significant fraction of the MSH2 VUS has lost MMR activity, suggesting pathogenicity, the large majority of the MSH6 VUS appears MMR proficient. We anticipate that this assay will be an important tool in the development of a comprehensive and widely applicable diagnostic procedure for LS-associated VUS.

KW - Biological Assay

KW - Blotting, Western

KW - Colorectal Neoplasms, Hereditary Nonpolyposis

KW - DNA-Binding Proteins

KW - Humans

KW - MutS Homolog 2 Protein

KW - Mutation, Missense

KW - Polymerase Chain Reaction

U2 - 10.1002/humu.22000

DO - 10.1002/humu.22000

M3 - Journal article

C2 - 22102614

SN - 1059-7794

VL - 33

SP - 488

EP - 494

JO - Human Mutation

JF - Human Mutation

IS - 3

ER -