Lynch Syndrome (LS) is an inherited predisposition to a range of cancers, notably uterine cancer in females and colorectal cancer (CRC) in both sexes, caused by a deficiency in mismatch repair (MMR). Germline mutations in several MMR genes predispose carriers to a high risk of CRC. Dr David Hughes (CSM / RCSI) collaborates with Mr Michael Farrell, a medical genetics counsellor at the Mater Private Hospital in Dublin, on studies of familial CRC such as LS and they have a new study recently accepted in the journal Familial Cancer that details the likely deleterious effect of a variant in one of these MMR genes*. Genetic counselling of at-risk individuals is optimally based on identification of the underlying deleterious germline mutation in an appropriate family member who has developed cancer. Approximately 25% of mismatch repair (MMR) variants are exonic nucleotide substitutions. Some result in the substitution of one amino acid for another in the protein sequence, so-called missense variants, while others are silent. The interpretation of the effect of missense and silent variants as deleterious or neutral is challenging. Pre-symptomatic testing for clinical use is not recommended for relatives of individuals with variants classified as ‘of uncertain significance’. These relatives, including non-carriers, are considered at high-risk as long as the contribution of the variant to disease causation cannot be determined. This results in continuing anxiety, and the application of potentially unnecessary screening and prophylactic interventions. This study details a large Irish Lynch syndrome kindred that carries the c.544A>G (p.Arg182Gly) alteration of uncertain significance in the MLH1 MMR gene. A systems approach is used to help define the likely significance of this variant by extensive testing of relevant family members in one kindred, immunohistochemical and molecular analysis of the effect of the variant change, a review of cancer incidence within three other LS kindreds carrying the same variant, and the use of in-silico prediction tools of likely harmfulness of a genetic change. The study results indicate that the hMLH1 p.Arg182Gly (c.544A>G) change causes LS and strongly supports reclassification of the variant as pathogenic.
*Clinical correlation and molecular evaluation confirm that the MLH1 p.Arg182Gly (c.544A/G) mutation is pathogenic and causes Lynch syndrome. Farrell MP, Hughes DJ, Berry IR, Gallagher DJ, Glogowski EA, Payne SJ, Kennedy MJ, Clarke RM, White SA, Muldoon CB, Macdonald F, Rehal P, Crompton D, Roring S, Duke ST, McDevitt T, Barton DE, Hodgson SV, Green AJ, Daly PA. Familial Cancer. 2012 Jul 7. [Epub ahead of print] PMID: 22773173