Evidence for classification of @entity72269 in @entity6756 as a neutral variant for XXXX .

@entity1 @entity6756 @entity124 @entity4309 @entity5 @entity72269 @entity4310 @entity14 @entity72270 @entity4638
BACKGROUND: @entity4309 ( @entity4309 ) is an autosomal dominant @entity4310 characterized by early onset @entity5 of the colorectum, endometrium and other @entity5 . A significant proportion of DNA variants in @entity4309 @entity1 are unclassified. Reports on the pathogenicity of the @entity72269 ( @entity72270 ) variant of the @entity6756 gene are conflicting. In this study, we provide new evidence indicating that this variant has no significant implications for @entity4309 . METHODS: The following approach was used to assess the clinical significance of the @entity72270 variant: frequency in a control population, case-control comparison, co-occurrence of the @entity72270 variant with a pathogenic mutation, co-segregation with the disease and @entity124 in @entity5 from carriers of the variant. We genotyped @entity72270 in 1034 individuals (373 sporadic @entity14 [ @entity14 ] @entity1 , 250 index subjects from families suspected of having @entity4309 [revised Bethesda guidelines] and 411 controls). Three well-characterized @entity4309 families that fulfilled the Amsterdam II Criteria and consisted of members with the @entity72270 variant were included to assess co-occurrence and co-segregation. A subset of @entity14 DNA samples from 17 @entity1 carrying the @entity72270 variant was screened for @entity124 using five mononucleotide markers. RESULTS: Twenty-seven individuals were heterozygous for the @entity72270 variant; nine had sporadic @entity14 (2.41%), seven were suspected of having hereditary @entity14 (2.8%) and 11 were controls (2.68%). There were no significant associations in the case-control and case-case studies. The @entity72270 variant was co-existent with pathogenic mutations in two unrelated @entity4309 families. In one family, the allele distribution of the pathogenic and unclassified variant was in trans, in the other family the pathogenic variant was detected in the @entity4638 gene and only the deleterious variant co-segregated with the disease in both families. Only two positive cases of @entity124 (2/17, 11.8%) were detected in @entity5 from @entity72270 carriers, indicating that this variant does not play a role in functional inactivation of @entity6756 in @entity14 @entity1 . CONCLUSIONS: The @entity72270 variant should be considered a neutral variant for @entity4309 . These findings have implications for the clinical management of @entity14 probands and their relatives.
