Evaluation of potential pathogenicity of missense variants found in the hMLH1 and hMSH2 genes
| Family/ patient | Gene/exon | DNA change | AA change | Nature AA change | Cons. residue | Frequency controls | Cosegregation with disease | Functional consequences | MSI (markers) | IHC |
|---|---|---|---|---|---|---|---|---|---|---|
| MSI, microsatellite instability; IHC, immunohistochemistry; AA, amino acid; NA, not available. | ||||||||||
| Novel mutations are represented in bold type. | ||||||||||
| *Family carrying two mutations (see results). | ||||||||||
| †Despite this mutation resulting in an amino acid change, it also results in an aberrant splicing leading to exon 17 deletion, as was previously described.26 | ||||||||||
| ‡Three or less affected members were available per family.12 | ||||||||||
| §All other affected members of the family were deceased, or unable to contact other family members.12 | ||||||||||
| Fam 1 | MLH1 exon 17 | CGA to CTA | R659L (aberrant splicing)† | Positive charged to aliphatic | Yes | 0/50 | Yes | Loss of function ref26 | High (2/5) | Abnormal |
| Fam 2 | MLH1 exon 16 | CTT to CAT | L607H | Neutral to charged | No | 0/50 | Yes | NA | Stable (0/5) | Normal |
| Fam 3 | MLH1 exon 8 | GTG to ATG | V213M | Non-polar to non-polar | No | 0/50 | Inconclusive‡ | NA | Stable (0/5) | Normal |
| Fam 4 | MLH1 exon 16 | AAG to ACG | K618T | Positive charged to non-polar | No | 0/50 | Inconclusive‡ | Loss of function13151627 | Stable (0/5) | Normal |
| Fam 5* | MSH2 exon 6 | GGC to GAC | G322D | Non-polar to negative charged | Yes | 0/50 | No | NA | High (5/5) | Abnormal |
| Fam 6 | MLH1 exon 12A | CGT to TGT | R385C | Polar to non-polar | No | 0/50 | Yes | NA | NA | NA |
| P 1 | MLH1 exon 16 | AAG to ACG | K618T | Positive charged to non-polar | No | 0/50 | Not possible§ | Loss of function13151627 | Stable (0/5) | Normal |
| P 2 | MLH1 exon 17 | CCC to TCC | P648S | Non-polar to polar | No | 3/50 | Not possible§ | NA | High (2/5) | Abnormal |
| P 3 | MSH2 exon 6 | GGC to GAC | G322D | Non-polar to negative charged | Yes | 0/50 | Not possible§ | NA | Stable (0/5) | Normal |
| P 4 | MSH2 intron 7 | AAG to CGG | — | — | — | 0/50 | Inconclusive‡ | NA | High (4/5) | Abnormal |