Loss of MSH2 and MSH6 due to heterozygous germline defects in MSH3 and MSH6

Familial Cancer
Monika MorakElke Holinski-Feder

Abstract

Lynch Syndrome (LS) is the most common dominantly inherited colorectal cancer (CRC) predisposition and is caused by a heterozygous germline defect in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. High microsatellite instability (MSI-H) and loss of MMR protein expression in tumours reflecting a defective MMR are indicators for LS, as well as a positive family history of early onset CRC. MSH2 and MSH6 form a major functional heterodimer, and MSH3 is an alternative binding partner for MSH2. So far, the role of germline MSH3 variants remains unclear, as to our knowledge heterozygous truncating variants are not regarded causative for LS, but were detected in patients with CRC, and recently biallelic MSH3 defects have been identified in two patients with adenomatous polyposis. By gene screening we investigated the role of MSH3 in 11 LS patients with truncating MSH6 germline variants and an unexplained MSH2 protein loss in their corresponding MSI-H tumours. We report the first two LS patients harbouring heterozygous germline variants c.1035del and c.2732T>G in MSH3 coincidentally with truncating variants in MSH6. In the patient with truncating germline variants in MSH3 and MSH6, two additional somatic second hi...Continue Reading

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Citations

Dec 12, 2019·European Journal of Human Genetics : EJHG·Anke Marie ArnoldElke Holinski-Feder
Oct 1, 2019·Case Reports in Oncological Medicine·Matthew KeatingKevan Hartshorn
Jul 3, 2021·International Journal of Molecular Sciences·Martina Lepore SignorileGiuseppe Ingravallo

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Methods Mentioned

BETA
PCR

Software Mentioned

Human Splice Site finder ( HSF )
SIFT
SoftGenetics
PolyPhen
ExAC browser
Mutation Taster
Mutation surveyor

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