Table 4.
Summary of tumors with discordant MSI and immunohistochemistry results
| IHC | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| MLH1 | MSH2 | MSH6 | PMS2 | MSI Status |
MLH1 Methylation |
Germline1 Alteration |
BRAF mutation |
Tumor Location |
Age | AC/FH | |
| 1 | + | + | + | + | MSI-H | Negative | MSH2 | Neg | Rectum | 48 | Neg/No |
| 2 | + | + | + | + | MSI-H | NP | NP | NP | Colon | 47 | Neg/No |
| 3 | + | + | + | + | MSI-H | Negative | MLH1 | NP | Colon | 62 | Pos/Yes |
| 4 | + | + | + | + | MSI-H | NP | MLH1, PMS2 | NP | Colon | 57 | Neg/No |
| 5 | + | + | + | + | MSI-H | Present | NP | NP | Small Bowel | 59 | Neg/No |
| 6 | + | + | + | + | MSI-H | NP | Negative | NP | Colon | 47 | Neg/Yes |
| 7 | + | + | + | + | MSI-H | Negative | MLH1 | Neg | Colon | 29 | Pos/Yes |
| 8 | + | + | + | + | MSI-H | NP | Negative | NP | Colon | 43 | Neg/Yes |
| 9 | + | + | + | + | MSI-H | Negative | Negative | Neg | Uterus | 51 | Neg/Yes |
| 10 | + | + | + | + | MSI-H | Negative | Negative | Neg | Colon | 63 | Neg/Yes |
| 11 | + | + | + | + | MSI-H | Negative | NP | Neg | Uterus | 32 | Pos/Yes |
| 12 | + | + | + | + | MSI-H | Negative | NP | Neg | Colon | 47 | Neg/Yes |
| 13 | − | + | + | − | MSS | Negative | Negative | Neg | Uterus | 85 | Neg/Yes |
Abbreviations: MSI, microsatellite instability; MSI-H, MSI-High; MSS, microsatellite stable; NP, not performed; Neg, negative; Pos, positive; AC, Amsterdam II Criteria; FH, family history of a Lynch Syndrome-associated cancer
The MLH1 mutation (618del [1852del3]) in Patient 3 is known to be pathogenic. This is an in-frame deletion of 3 nucleotides that results in the omission of lysine from amino acid position 618, but does not lead to premature protein termination. The germline alterations in Patients 1, 4, and 7 are currently classified as variants of undetermined significance. For Patient 1, there is a point mutation (T677R) that substitutes arginine for threonine at 677. For Patient 4, three different mutations were identified, one in PMS2 (PMS2 c. 1437C>G [p.His479Gln]) and two in MLH1 (MLH1 c.290A>G [p.Tyr97Cys] and MLH1 c.299G>A [R100Q, Arg100Gln]); none of these are currently predicted to result in protein truncation. Patient 7 had an inframe duplication of exons 3–5 of MLH1. This is not predicted to cause protein truncation, but it possible that the duplication would affect protein function. Patients 6 and 10 had negative MLH1, MSH2, and MSH6 germline testing. Patient 8 had negative MLH1, MSH2, MSH6, and PMS2 germline testing. Patient 9 had negative MSH6 germline testing. Patient 13 had negative and MLH1 and MSH2 germline testing and declined further testing.