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Table 1 Comparison of published functional and clinical data on hMLH1 variants

From: Assessing pathogenicity of MLH1 variants by co-expression of human MLH1 and PMS2genes in yeast

MLH1 alteration Functional and biochemical assays Clinical data
  Assay type Outcomea MSIb MLH1 IHCc Aged Family history/segregation Ref.
A92Pe        [30]
S93G In vivo MMR assay [11, 10] - -    70 YES/ [9]
  In vitro MMR assay [11, 9, 3] - - - YES POS 90 YES/ [32]
  In vitro protein interaction assay [9, 3] - - YES NEG 53 YES/ [32]
  MLH1 expression/localization [11, 9] - -      [33]
      65 YES/YES [3]
T117Me In vivo MMR assay [11, 13] + + YES     [34]
  In vitro MMR assay [11, 12] + +    40 YES/ [35]
  In vivo protein interaction assay [7] + YES NEG 43 YES/ [36]
  In vitro protein interaction assay [7, 12] ± ± NO POS 42 YES/ [36]
  MLH1 expression/localization [11, 7, 13, 16] + + + + YES    YES/ [37]
    YES POS 55 YES/ [38]
    YES NEG    [39]
I219V In vivo MMR assay [11, 13] - -   POS 55   [36]
  In vitro MMR assay [11, 9, 12] - - -      
  In vivo protein interaction assay [7] -      
  In vitro protein interaction assay [9, 12] - -      
  MLH1 expression/localization [11, 9] ± -      
K618Re    YES NEG    [40]
      < 50 NO/ [41]
K618Te In vivo MMR assay [11, 13] + + NO POS   YES/NO [43]
  In vitro MMR assay [11, 9] ± - NO POS   YES/NO [44]
  In vivo protein interaction assay [7] -    42 NO/ [45]
  In vitro protein interaction assay [7, 42, 9, 12] + + - +      
  MLH1 expression/localization [11, 7, 13, 9] ± ± ± ±      
Y646C In vitro MMR assay [9] - YES NEG 48 YES/ [46]
  In vitro protein interaction assay [9, 6] - + YES NEGf 36 YES/ [9, 47]
  MLH1 expression/localization [9, 6] - - YES NEG 48 YES/ [6]
    YES NEG 51 YES/ [6]
R659Qe In vivo MMR assay [11] ± YES NEG 32 YES/ [9]
  In vitro MMR assay [11, 9] - -      
  In vitro protein interaction assay [9] -      
  MLH1 expression/localization [11, 9] ± -      
  1. aThe outcome of each assay is given: +, pathogenic; -, non-pathogenic; ±, inconclusive. Each symbol refers to the assay referenced in section: Assay type.
  2. bMicrosatellite instability.
  3. cImmunohistochemical staining of MLH1: POS, positive; NEG, negative.
  4. dPatients' age at cancer onset.
  5. eThe variant was also found in patients carrying a second MMR alteration. Those patients were excluded from the Table.
  6. fImmunohistochemical staining of PMS2. In this case MLH1 staining was positive.