Assessing the pathogenicity of MLH1 missence mutations in patients with suspected Hereditary Non-Polyposis Colorectal Cancer (HNPCC): correlation with clinical, genetic and functional features

Research output: Contribution to journalArticle


  • L Belvederesi
  • F Bianchi
  • C Loretelli
  • D Gagliardini
  • E Galizia
  • B Bracci
  • S Rosati
  • I Bearzi
  • A Viel
  • R Cellerino

Colleges, School and Institutes


Assessing the pathogenicity of missense mutations of MLH1 and MSH2 is critical to counsel patients with suspected hereditary nonpolyposis colorectal cancer (HNPCC). Approximately 32% of all MLH1 mutations and 18% of MSH2 mutations are missense variants which often have an uncertain genetic significance. To assess the pathogenicity of four MLH1 missense mutations which were found in five patients with suspected HNPCC, P648S (CCC-TCC), L559R (CTG-CGG), K618A (AAG-GCG), Y646C (TAT-TGT), we studied their ability to disrupt MLH1 protein function and their relationship with all those clinical, genetic and pathological features which are typical of this syndrome. Our results indicated that the P648S and L559R mutations were probably pathogenic because they disrupted MLH1 protein interaction with its partner PMS2 in vitro and abolished MLH1 expression in HCT116 cells. In addition these variants were associated with features often found in HNPCC patients: in particular high microsatellite instability, occurrence of high grade tumours and, in one case, strong family history. The pathogenicity of the K618A and Y646C mutations was questionable as their correlation with features typical of HNPCC was low and the outcome of the functional analysis was ambiguous. These observations suggested that a clinically usable assessment of the pathogenicity of MLH missense variants can be achieved through the analysis of multiple mutation characteristics among which loss of protein function, occurrence of microsatellite instability and family history seemed to have a predominant role.


Original languageEnglish
Pages (from-to)853-859
Number of pages7
JournalEuropean Journal of Human Genetics
Publication statusPublished - 17 May 2006


  • HNPCC, MLH1, missense mutation