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.

Short term psychological distress in patients actively approached for genetic counselling after diagnosis of breast cancer.

This prospective study assessed anxiety, depression and breast cancer-specific distress in recently diagnosed breast cancer patients before and after an active approach for genetic counselling at the beginning of adjuvant radiotherapy (mean: 52 days after surgery). Patients completed the hospital anxiety and depression scale (HADS) and the impact of event scale (IES). Psychological distress did not increase after the approach. High anxiety decreased in the comparison group (n=182), whereas breast cancer specific distress decreased in the approached group (n=220). It is concluded that breast cancer patients can be approached for genetic counselling shortly after surgery without additional short-term psychological burden. Patients who are young, single with little social support, less optimistic, use an avoiding coping style, experience a lower quality of life or who are highly distressed prior to approach for genetic counselling, need extra attention. Medical history did not prove to be relevant.