A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype

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

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


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 biallelic truncating mutations. Residual expression of fulllength 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.

Original languageEnglish
Pages (from-to)348-352
Number of pages5
JournalJournal of Medical Genetics
Issue number5
StatePublished - 2015
Externally publishedYes


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