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Digenic inheritance of MSH6 and MUTYH variants in familial colorectal cancer
Author(s) -
Schubert Stephanie A.,
Ruano Dina,
Tiersma Yvonne,
Drost Mark,
Wind Niels,
Nielsen Maartje,
Hest Liselotte P.,
Morreau Hans,
Miranda Noel F. C. C.,
Wezel Tom
Publication year - 2020
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.22883
Subject(s) - mutyh , msh6 , lynch syndrome , genetics , colorectal cancer , cancer , exome sequencing , medicine , biology , germline mutation , oncology , dna mismatch repair , gene , mutation
We describe a family severely affected by colorectal cancer (CRC) where whole‐exome sequencing identified the coinheritance of the germline variants encoding MSH6 p.Thr1100Met and MUTYH p.Tyr179Cys in, at least, three CRC patients diagnosed before 60 years of age. Digenic inheritance of monoallelic MSH6 variants of uncertain significance and MUTYH variants has been suggested to predispose to Lynch syndrome‐associated cancers; however, cosegregation with disease in the familial setting has not yet been established. The identification of individuals carrying multiple potential cancer risk variants is expected to rise with the increased application of whole‐genome sequencing and large multigene panel testing in clinical genetic counseling of familial cancer patients. Here we demonstrate the coinheritance of monoallelic variants in MSH6 and MUTYH consistent with cosegregation with CRC, further supporting a role for digenic inheritance in cancer predisposition.