Genes that are homologs to E. coli DNA mismatch repair gene mutL:
(1) PMS2: postmeiotic segregation increased 2 (S. cerevisiae) on 7p22.2
(2) PMS1 (MLH2)
(3) MLH1: mutL homolog 1, colon cnacer, nonpolyposis type 2 (E. coli) on 3p21.3
Heterodimers formed by proteins expressed:
(1) mutL alpha: MLH1/PMS2
(2) mutL beta: MLH1/PMS1
(3) mutL gamma: MLH1/MLH3
Genes that are homologs to E. coli DNA mismatch repair gene mutS:
(1) MSH2: mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) on 2p21
(2) MSH3
(3) GTBP (MSH6): mutS homolog 6 (E. coli) on 2p16
Heterodimers formed by proteins expressed:
(1) mutS alpha: MSH2/MSH6
(2) mutS beta: MSH2/MSH3
Immunohistochemical staining is typically performed using a panel of antibodies against:
(1) MLH1
(2) PMS2
(3) MSH2
(4) MSH6
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Protein with Absent Staining
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Seen with
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Probable MSI Phenotype
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Lynch Syndrome
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none (all present)
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MSS or MSI-L
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unlikely (probably sporadic)
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MLH1 and PMS2
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MLH1 germline mutation OR promoter hypermethylation
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MSI-H
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possible (may be sporadic)
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PMS2
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germline PMS2 mutation
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MSI-H
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Yes
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MSH2
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germline MSH2 mutation
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MSI-H
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Yes
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MSH6
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germline MSH6 mutation
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MSI-H
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Yes
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If MLH1 expression is lost, then test for BRAF mutation V600E. If present then Lynch syndrome unlikely.
If Lynch Syndrome is possible, then refer to a genetic counselor.
Additional testing may be needed:
(1) To detect mutations in other mismatch repair proteins (MSH3, MLH2).
(2) To detect CpG island methylator phenotype (seen in sporadic cancers).
(3) To sequence the mismatch repair genes.
