Cancer risks by gene, age and gender in 6,350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

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Pathogenic variants affecting MLH1, MSH2, MSH6 and PMS2 cause Lynch Syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer.
We conducted an international, multicentre prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6,350 participants and 51,646 follow-up years.
There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2
variants caused high penetrance dominant cancer syndromes sharing similar
colorectal, endometrial and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastro-intestinal tract, brain and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial or ovarian cancer.
Management guidelines for Lynch Syndrome may require revision in light of these different gene and gender specific risks and the good prognosis for the most commonly associated cancers.

Bibliographical metadata

Original languageEnglish
JournalGenetics in Medicine
Early online date24 Jul 2019
Publication statusPublished - 2019