Clinical classification of coding variants
| A. Classification | |||||
| Class | Genes (%) | Total | |||
| MLH1 | MSH2 | MSH6 | PMS2 | ||
| Pathogenic | 0 (0.0) | 3 (1.2) | 2 (0.4) | 8 (3.7) | 13 (1.1) |
| Likely pathogenic | 1 (0.5) | 1 (0.4) | 4 (0.8) | 5 (2.3) | 11 (0.9) |
| VUS | 113 (53.8) | 118 (47.6) | 193 (39.1) | 83 (38.6) | 507 (43.5) |
| Likely benign | 48 (22.9) | 50 (20.2) | 89 (18.1) | 53 (24.7) | 240 (20.6) |
| Benign | 7 (3.3) | 11 (4.4) | 8 (1.6) | 17 (7.9) | 42 (3.6) |
| Conflicting | 8 (3.8) | 22 (8.9) | 24 (4.9) | 31 (14.4) | 85 (7.3) |
| Unclassified | 33 (15.7) | 43 (17.3) | 173 (35.1) | 19 (8.8) | 268 (23.0) |
| Total | 210 (100.0) | 248 (100.0) | 493 (100.0) | 215 (100.0) | 1166 (100.0) |
| B. List of Pathogenic/Likely pathogenic variants | |||||
| Base change | Amino acid change* | Variation type | Variant class | Carrier | Carrier rate (%)† |
| MLH1 | |||||
| c.1984A>G | p.Thr662Ala | Nonsynonymous | Likely pathogenic | 1 | 0.005 |
| MSH2 | 0.032 | ||||
| c.28C>T | p.Gln10Ter | Nonsense | Pathogenic | 1 | |
| c.82G>A | p.Glu28Lys | Nonsynonymous | Likely pathogenic | 3 | |
| c.645+1G>A | – | Splice donor | Pathogenic | 1 | |
| c.1457_1460delATGA | p.Asn486fs | Frameshift deletion | Pathogenic | 1 | |
| MSH6 | 0.053 | ||||
| c.1807A>T | p.Lys603Ter | Stopgain | Likely pathogenic | 1 | |
| c.1838T>A | p.Leu613Ter | Stopgain | Pathogenic | 1 | |
| c.2095G>T | p.Glu699Ter | Stopgain | Likely pathogenic | 1 | |
| c.2906A>G | p.Tyr969Cys | Missense | Likely pathogenic | 1 | |
| c.3226C>T | p.Arg1076Cys | Missense | Likely pathogenic | 5 | |
| c.3253dupC | p.Thr1085fs | Frameshift insertion | Pathogenic | 1 | |
| PMS2 | 0.085 | ||||
| c.1A>G | p.Met1Val | Missense | Likely pathogenic | 1 | |
| c.2T>A | p.Met1Lys | Missense | Pathogenic | 1 | |
| c.164–1G>C | – | Splice acceptor | Likely pathogenic | 1 | |
| c.673G>T | p.Glu225Ter | Stopgain | Pathogenic | 1 | |
| c.825A>G | p.Gln275= | Synonymous | Likely pathogenic | 4 | |
| c.903+2T>C | – | Splice donor | Likely pathogenic | 1 | |
| c.993C>A | p.Cys331Ter | Stopgain | Pathogenic | 1 | |
| c.1240dupT | p.Asp414fs | Frameshift insertion | Pathogenic | 1 | |
| c.1687C>T | p.Arg563Ter | Stopgain | Pathogenic | 1 | |
| c.1731dupT | p.Arg578fs | Frameshift insertion | Pathogenic | 1 | |
| c.1864_1865delAT | p.Met622Glufs*5 | Frameshift deletion | Pathogenic | 1 | |
| c.1959T>A | p.Cys653Ter | Stopgain | Pathogenic | 1 | |
| c.2276-2A>C | – | Splice acceptor | Likely pathogenic | 1 | |
| C. Distribution of Pathogenic/Likely pathogenic variants | |||||
| Item | Genes (%) | Total (%) | |||
| MLH1 | MSH2 | MSH6 | PMS2 | ||
| Colon and rectal cancer | 0 (0.0) | 1 (7.1) | 3 (21.4) | 7 (50.0) | 11 (78.6) |
| LS/HNPCC | 0 (0.0) | 2 (14.3) | 2 (14.3) | 1 (7.1) | 5 (35.7) |
| Breast cancer | 0 (0.0) | 0 (0.0) | 0 (0.0) | 3 (21.4) | 3 (21.4) |
| Endometrial cancer | 0 (0.0) | 0 (0.0) | 2 (14.3) | 2 (14.3) | 4 (28.6) |
| Suspected LS | 0 (0.0) | 1 (7.1) | 0 (0.0) | 2 (14.3) | 3 (21.4) |
| Ovarian cancer | 0 (0.0) | 0 (0.0) | 1 (7.1) | 1 (7.1) | 2 (14.3) |
| Gastric cancer | 0 (0.0) | 0 (0.0) | 1 (7.1) | 0 (0.0) | 1 (7.1) |
| Glioblastoma | 0 (0.0) | 0 (0.0) | 1 (7.1) | 0 (0.0) | 1 (7.1) |
| Brain cancer | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (7.1) | 1 (7.1) |
| Duodenal cancer | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (7.1) | 1 (7.1) |
| Total | 0 (0.0) | 3 (21.4) | 3 (21.4) | 8 (57.1) | 14 (100.0) |
*Variants marked ‘–’ were predicted by InterVar.
†
HNPCC, hereditary nonpolyposis colorectal cancer; LS, Lynch syndrome; VUS, variants of unknown significance.