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A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome.

van Riel E, Ausems MG, Hogervorst FB, Kluijt I, van Gijn ME, van Echtelt J, Scheidel-Jacobse K, Hennekam EF, Stulp RP, Vos YJ, Offerhaus GJ, Menko FH, Gille JJ - Hered Cancer Clin Pract (2010)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Genetics, University Medical Centre Utrecht, Lundlaan 6, Utrecht, The Netherlands. E.vanRiel@umcutrecht.nl.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Pedigree from Family 4 (NKI F1390). Co = colon cancer.
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Figure 4: Pedigree from Family 4 (NKI F1390). Co = colon cancer.

Mentions: Probands of these six families were referred to a Family Cancer Clinic for genetic counselling because of a personal and/or family history of cancer. A detailed pedigree analysis was performed and, if possible, medical data of affected relatives were verified (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6). For all affected relatives clinical data were recorded including sex, type of cancer, age at diagnosis or at death.


A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome.

van Riel E, Ausems MG, Hogervorst FB, Kluijt I, van Gijn ME, van Echtelt J, Scheidel-Jacobse K, Hennekam EF, Stulp RP, Vos YJ, Offerhaus GJ, Menko FH, Gille JJ - Hered Cancer Clin Pract (2010)

Pedigree from Family 4 (NKI F1390). Co = colon cancer.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2927519&req=5

Figure 4: Pedigree from Family 4 (NKI F1390). Co = colon cancer.
Mentions: Probands of these six families were referred to a Family Cancer Clinic for genetic counselling because of a personal and/or family history of cancer. A detailed pedigree analysis was performed and, if possible, medical data of affected relatives were verified (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6). For all affected relatives clinical data were recorded including sex, type of cancer, age at diagnosis or at death.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Genetics, University Medical Centre Utrecht, Lundlaan 6, Utrecht, The Netherlands. E.vanRiel@umcutrecht.nl.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus