A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome.
BACKGROUND
An unclassified variant (UV) in exon 1 of the MLH1 gene, c.112A > C, p.Asn38His, was found in six families who meet diagnostic criteria for Lynch syndrome. The pathogenicity of this variant was unknown. We aim to elucidate the pathogenicity of this MLH1 variant in order to counsel these families adequately and to enable predictive testing in healthy at-risk relatives.


METHODS
We studied clinical data, microsatellite instability and immunohistochemical staining of MMR proteins, and performed genealogy, haplotype analysis and DNA testing of control samples.


RESULTS
The UV showed co-segregation with the disease in all families. All investigated tumors showed a microsatellite instable pattern. Immunohistochemical data were variable among tested tumors. Three families had a common ancestor and all families originated from the same geographical area in The Netherlands. Haplotype analysis showed a common haplotype in all six families.


CONCLUSIONS
We conclude that the MLH1 variant is a pathogenic mutation and genealogy and haplotype analysis results strongly suggest that it is a Dutch founder mutation. Our findings imply that predictive testing can be offered to healthy family members. The immunohistochemical data of MMR protein expression show that interpreting these results in case of a missense mutation should be done with caution.
van Riel
Els
E
Department of Medical Genetics, University Medical Centre Utrecht, Lundlaan 6, Utrecht, The Netherlands. E.vanRiel@umcutrecht.nl.
Ausems
Margreet Gem
MG
Hogervorst
Frans Bl
FB
Kluijt
Irma
I
van Gijn
Marielle E
ME
van Echtelt
Jeanne
J
Scheidel-Jacobse
Karen
K
Hennekam
Eric Fam
EF
Stulp
Rein P
RP
Vos
Yvonne J
YJ
Offerhaus
G Johan A
GJ
Menko
Fred H
FH
Gille
Johan Jp
JJ