We aimed to determine the pathogenicity of previously reported variants (c.-28A>G and c.-7C>T) within the MLH1 5'untranslated region (UTR) in two individuals from unrelated suspected Lynch syndrome families.
We aimed to determine the pathogenicity of previously reported variants (c.-28A>G and c.-7C>T) within the MLH1 5'untranslated region (UTR) in two individuals from unrelated suspected Lynch syndrome families.
We aimed to determine the pathogenicity of previously reported variants (c.-28A>G and c.-7C>T) within the MLH1 5'untranslated region (UTR) in two individuals from unrelated suspected Lynch syndrome families.
A dominantly transmitted constitutional MLH1 epimutation has been linked to an MLH1 haplotype bearing two single-nucleotide variants, NM_000249.2: c.-27C>A and c.85G>T, in a Caucasian family with Lynch syndrome from Western Australia.
Evidence from clinical, histological, immunohistochemical, and molecular genetic data suggests that MLH1 c.1664T>C (p.Leu555Pro) is likely to be the pathogenic cause of Lynch syndrome in this family.
Evidence from clinical, histological, immunohistochemical, and molecular genetic data suggests that MLH1 c.1664T>C (p.Leu555Pro) is likely to be the pathogenic cause of Lynch syndrome in this family.
We encountered a large Irish Lynch syndrome kindred that carries the c.544A>G (p.Arg182Gly) alteration in the MLH1 gene and we undertook to study the variant.
The pathogenicity of the K618A and Y646C mutations was questionable as their correlation with features typical of HNPCC was low and the outcome of the functional analysis was ambiguous.
We herein describe a nucleotide change, c.2063T>G in exon 13 of the MSH2 gene, present in families that fulfill the Amsterdam criteria for Lynch syndrome and originate from northern Tenerife (Canary Islands-Spain).
In this study, we show segregation of the putative pathogenic MSH6 missense mutation c.1346T>C p.Leu449Pro with microsatellite instability-high Lynch syndrome-related tumours lacking MSH6 expression in a large 17th century pedigree.
In this study, we show segregation of the putative pathogenic MSH6 missense mutation c.1346T>C p.Leu449Pro with microsatellite instability-high Lynch syndrome-related tumours lacking MSH6 expression in a large 17th century pedigree.
In contrast, the third amino-terminal mutation S93G did not affect the heterodimerization, and the MLH1(S93G)/PMS2 variant was functional in the in vitro MMR assay, given thus the nature of the HNPCC family in question.
Interestingly, two HNPCC missense alterations (Q542L and L582V) contained within the consensus interaction region displayed no effect on interaction with hPMS2, suggesting that they may affect other functions of hMLH1.
To evaluate the mutL homolog 1 (MLH1) I219V polymorphism in 124 unrelated South American individuals suspected of having Lynch syndrome, based on frequency, association with pathogenic MLH1 and mutS homolog 2 (MSH2) mutation and clinical features.
Although rare in the general population, A636P mutations are found at increased frequency in Ashkenazim with a personal or family history of colorectal or other HNPCC-associated cancers.
The approach was validated by transfecting cDNA of wild-type (WT) MLH1, cDNAs bearing two previously identified polymorphisms (I219V and I219L) and two with confirmed hereditary nonpolyposis colorectal cancer (HNPCC) syndrome mutations (G224D and G67R).
Analysis of seven HNPCC-associated hMLH1 missense mutations located within the hMRE11-interacting domain shows that four mutations (L574P, K618T, R659P and A681T) cause near-complete disruption of the interaction between hMRE11 and hMLH1, and two mutations (Q542L and L582V) cause a 30% reduction of protein interaction.
Although rare in the general population, the A636P mutation is detected in up to 7% of Ashkenazi Jewish patients with early age-of-onset colorectal cancer, and may account for up to one third of HNPCC in the Ashkenazi Jewish population.
Interestingly, two HNPCC missense alterations (Q542L and L582V) contained within the consensus interaction region displayed no effect on interaction with hPMS2, suggesting that they may affect other functions of hMLH1.
We conclude that MLH1 K618A is not a fully penetrant Lynch syndrome mutation, although it is not without effect, appearing to increase the risk of Lynch syndrome-associated tumors approximately twofold.