MLH1 c.27G>A (p.Arg9=) is a synonymous likely/pathogenic variant underlying variably mosaic constitutional MLH1 methylation in Lynch syndrome.

ABSTRACT: The MLH1 synonymous variant c.27G>A (p.Arg9 =) has been reported in four index cases with suspected Lynch syndrome, but is variably classified as "likely pathogenic" or "variant of uncertain significance" due to insubstantial clinical and functional evidence. We report three new MLH1 c.27G>A index cases with family histories fulfilling Amsterdam criteria for Lynch syndrome and reassessed collective evidence for pathogenicity. Two are European families from the UK (two siblings) and Spain (three members spanning three generations), and the third is a proband from Mongolia, the first non-European reported with this variant. Blood-based constitutional MLH1 methylation testing in six heterozygotes from the three families revealed varying levels of mosaic methylation, even within the same famil

SUBMITTER: Alvarez R 

PROVIDER: S-EPMC12330223 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature