Reclassification of Two MLH1 Variants of Uncertain Significance Utilizing Clinical and Functional Data.

ABSTRACT:

Background

Pathogenic variants in the mismatch repair genes are associated with an elevated lifetime risk of colorectal cancer (CRC). We previously identified two variants of uncertain significance (VUS) in the MLH1 gene, c.696_698del, p.(Cys233del) and c.1919C > G, p.(Pro640Arg), in Danish families with numerous occurrences of CRC.

Methods

To reclassify the variants we collected clinical data, initiated tumor and co-segregation analysis, and performed RNA splicing analysis, subcellular localization, and protein stability studies.

Results

The functional analysis revealed that the c.696_698del, p.(Cys233del) variant had an effect at the RNA level, on subcellular localization, and on protein stability, while the c.1919C > G, p.(Pro640Arg) variant showed decreased expres

SUBMITTER: Frederiksen JH 

PROVIDER: S-EPMC11567815 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature