Incomplete segregation of MSH6 frameshift variants with phenotype of lynch syndrome

Raffaella Liccardo, Marina De Rosa, Giovanni Battista Rossi, Nicola Carlomagno, Paola Izzo, Francesca Duraturo

Research output: Contribution to journalArticlepeer-review


Lynch syndrome (LS), the most frequent form of hereditary colorectal cancer, involves mutations in mismatch repair genes. The aim of this study was to identify mutations in MSH6 from 97 subjects negative for mutations in MLH1 and MSH2. By direct sequencing, we identified 27 MSH6 variants, of which, nine were novel. To verify the pathogenicity of these novel variants, we performed in silico and segregation analyses. Three novel variants were predicted by in silico analysis as damaging mutations and segregated with the disease phenotype; while a novel frameshift deletion variant that was predicted to yield a premature stop codon did not segregate with the LS phenotype in three of four cases in the family. Interestingly, another frame-shift variant identified in this study, already described in the literature, also did not segregate with the LS phenotype in one of two affected subjects in the family. In all affected subjects of both families, no mutation was detected in other MMR genes. Therefore, it is expected that within these families, other genetic factors contribute to the disease either alone or in combination with MSH6 variants. We conclude that caution should be exercised in counseling for MSH6-associated LS family members.

Original languageEnglish
Article number999
JournalInternational Journal of Molecular Sciences
Issue number5
Publication statusPublished - May 6 2017


  • Hereditary colorectal cancer
  • Lynch syndrome
  • MSH6 gene
  • Oligogenic model
  • Segregation analysis

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Computer Science Applications
  • Spectroscopy
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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