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Description and functional analysis of a novel in frame mutation linked to hereditary non-polyposis colorectal cancer
  1. T E Raevaara1,
  2. T Timoharju1,
  3. K E Lönnqvist1,
  4. R Kariola1,
  5. M Steinhoff2,
  6. R M W Hofstra3,
  7. E Mangold2,
  8. Y J Vos4,
  9. M Nyström-Lahti1
  1. 1Division of Genetics, Department of Biosciences, University of Helsinki, Finland
  2. 2Institute of Human Genetics, University of Bonn, Germany
  3. 3Department of Medical Genetics, University of Groningen, The Netherlands
  4. 4Department of Clinical Genetics, Groningen University Hospital, The Netherlands
  1. Correspondence to:
 Dr M Nyström-Lahti, Division of Genetics, Department of Biosciences, PO Box 56 (Viikinkaari 5), FIN-00014 University of Helsinki, Finland;
 minna.nystrom-lahti{at}helsinki.fi

https://doi.org/10.1136/jmg.39.10.747

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    Key points

    • Hereditary non-polyposis colorectal cancer (HNPCC) is characterised by a dominantly inherited predisposition to early onset cancer and is linked with malfunction of postreplicative DNA mismatch repair (MMR). A significant proportion of HNPCC associated mutations in the MMR genes give rise to single amino acid substitutions or in frame deletions, which are difficult to interpret.

    • It can be attempted to distinguish pathogenic non-truncating mutations from polymorphisms by segregation studies. Also, the biochemical characterisation of a substitution as well as the evolutionary conservation status of a mutated sequence may give some suggestion of its pathogenicity. However, reliable assessment of pathogenicity requires a functional test.

    • We describe here a novel MLH1 mutation, del GAA at codon 71, which was found in two typical HNPCC families. Since the mutation had not been reported before and the predicted coding change was a deletion of only one evolutionarily non-conserved amino acid, the pathogenicity of the mutation was assessed in a functional test. Both the interaction of the MLH1 variant (del71) with the normal PMS2 protein and the functionality of the heterodimer of MLH1 and PMS2 (MutLα) were studied.

    • While the heterodimerisation was not abolished, the MutLα-del71 variant was completely deficient in an in vitro MMR assay. The result of the functional assay thus confirms the pathogenicity of MLH1 del71, which is compatible with the typical HNPCC phenotype linked to the mutation.

    Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common cancer syndromes. The cancer susceptibility is dominantly inherited and associated with germline mutations in mismatch repair (MMR) genes. An inherited defect in one allele of a MMR gene and an acquired defect in the other allele leads to hypermutability associated with marked microsatellite instability (MSI) that accelerates tumour progression.1 To date, over 400 different mutations, affecting mostly the MMR genes MLH1 …

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