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 Lili Li A1 Nancy Hamel A1 Kristi Baker A1 Michael J McGuffin A1 Martin Couillard A1 Adrian Gologan A1 Victoria A Marcus A1 Bernard Chodirker A1 Albert Chudley A1 Camelia Stefanovici A1 Anne Durandy A1 Robert A Hegele A1 Bing-Jian Feng A1 David E Goldgar A1 Jun Zhu A1 Marina De Rosa A1 Stephen B Gruber A1 Katharina Wimmer A1 Barbara Young A1 George Chong A1 Marc D Tischkowitz A1 William D Foulkes 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.