RT Journal Article SR Electronic T1 A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 348 OP 352 DO 10.1136/jmedgenet-2014-102934 VO 52 IS 5 A1 Li, Lili A1 Hamel, Nancy A1 Baker, Kristi A1 McGuffin, Michael J A1 Couillard, Martin A1 Gologan, Adrian A1 Marcus, Victoria A A1 Chodirker, Bernard A1 Chudley, Albert A1 Stefanovici, Camelia A1 Durandy, Anne A1 Hegele, Robert A A1 Feng, Bing-Jian A1 Goldgar, David E A1 Zhu, Jun A1 De Rosa, Marina A1 Gruber, Stephen B A1 Wimmer, Katharina A1 Young, Barbara A1 Chong, George A1 Tischkowitz, Marc D A1 Foulkes, William D YR 2015 UL http://jmg.bmj.com/content/52/5/348.abstract AB Background Inherited mutations in DNA mismatch repair genes predispose to different cancer syndromes depending on whether they are mono-allelic or bi-allelic. This supports a causal relationship between expression level in the germline and phenotype variation. As a model to study this relationship, our study aimed to define the pathogenic characteristics of a recurrent homozygous coding variant in PMS2 displaying an attenuated phenotype identified by clinical genetic testing in seven Inuit families from Northern Quebec. Methods Pathogenic characteristics of the PMS2 mutation NM_000535.5:c.2002A>G were studied using genotype–phenotype correlation, single-molecule expression detection and single genome microsatellite instability analysis. Results This PMS2 mutation generates a de novo splice site that competes with the authentic site. In homozygotes, expression of the full-length protein is reduced to a level barely detectable by conventional diagnostics. Median age at primary cancer diagnosis is 22 years among 13 NM_000535.5:c.2002A>G homozygotes, versus 8 years in individuals carrying bi-allelic truncating mutations. Residual expression of full-length PMS2 transcript was detected in normal tissues from homozygotes with cancers in their 20s. Conclusions Our genotype–phenotype study of c.2002A>G illustrates that an extremely low level of PMS2 expression likely delays cancer onset, a feature that could be exploited in cancer preventive intervention.