Confirmation of damaging effect of MSH2 c.2634+1G>C mutation on splicing, its classification and implications for counseling.

INTRODUCTION

Lynch syndrome (LS) is predisposing mainly to colorectal and endometrial carcinomas, but also to urinary tract cancers. LS association with upper urinary tract carcinomas is known, but its association with bladder cancer is not so clear. Confirmation of pathogenicity of detected mutations in LS-associated genes is required for adequate counseling.

MATERIAL AND

METHODS

Tested young female has family history of two early colorectal and two bladder carcinomas. NGS sequencing revealed MSH2 splice site mutation c.2634+1G>C, which was confirmed by Sanger sequencing. MSH2 cDNA part containing potential splicing change was sequenced. in silico softwares were used to predict the effect of detected mutation on splicing and protein structure. ACMG Guidelines were used for mutation classification.

RESULTS

in silico softwares predict damaging effect of detected mutation on splicing and loss of protein-binding domains. cDNA sequencing confirmed this mutation causes exon 15 excision. ACMG Guidelines classify this mutation as Pathogenic.

DISCUSSION: MSH2 c.2634+1G>C mutation was not reported previously as LS associated. We confirmed its damaging effect on splicing. in silico tools predict consequent loss of protein domains implicating disrupted protein function. Our results suggest that this mutation should be classified as Pathogenic, and indicate inclusion of bladder cancer in LS cancer spectrum.