Table 2. Distribution of 99 identified germline variants from 40 CRC genes by case tiers.
| FCCTX-like cases | Lynch-like cases | ||||||
|---|---|---|---|---|---|---|---|
| Tier | Tier 1 | Tier 3 | Tier 4 | Tier 5 | Tier 2 | Tier 6 | |
| Criteria | AC-I | AC-I (no age)** | AC-II | CRC<60 ≥1 FDR/SDR |
AC-I/II | CRC ≥1 FDR/SDR |
|
| MSI status | MSS | MSS | MSS | MSS | MSI-H | MSI-H | |
| Established CRC genes | All variants | 7 (5.0%) | 12 (5.9%) | 2 (5.6%) | 18 (3.6%) | 7 (10.9%) | 3 (2.9%) |
| ACMG pathogenic variants | 1 (0.7%) | 3 (1.5%) | 1 (2.8%) | 3 (0.6%) | 4 (6.3%) | 1 (1.0%) | |
| Genes with variants | APC, MLH1, MSH2*, POLE, TGFBR2 | MLH3*, MSH2, MSH6*, POLD1, POLE | MUTYH, POLE* | APC*, AXIN2, MLH1, MLH3, MSH2*, MSH6, MUTYH, POLD1, POLE* | MLH1*, MSH2*, MSH6* | MLH1, MSH2, MSH6* | |
| Candidate CRC genes | All variants | 7 (5.0%) | 13 (6.4%) | 3 (8.3%) | 24 (4.8%) | 3 (4.7%) | 7 (6.7%) |
| ACMG pathogenic variants | - | 1 (0.5%) | 1 (2.8%) | 4 (0.8%) | - | 2 (1.9%) | |
| Genes with variants | ALPK2, CDH1, LAMA2, MSH3, NOS1, PREX1 | ALPK2, BLM, LAMA2, MSH3, NOS1, PALB2, POLQ, PTCH1, SH2B3* | LAMA2, MSH3, SH2B3* | ALPK2, BAP1, BLM, CDH1, HELQ, LAMA2, LRIG1, MSH3, NOS1*, POLQ*, PREX1, PTCH1, SH2B3* | HELQ, PALB2, PTCH1 | CHEK2*, ENG, LAMA2, LRIG1, MSH3, NOS1, POLQ* | |
| All ACMG pathogenic variants | 1/139 (0.7%) | 4/202 (2.0%) | 2/36 (5.6%) | 7/501 (1.4%) | 4/64 (6.3%) | 3/104 (2.9%) | |
| All variants | 14/139 (10.0%) | 25/202 (12.4%) | 5/36 (13.9%) | 42/501 (8.4%) | 10/64 (15.6%) | 10/104 (9.6%) | |
*Genes with ACMG classified mutations.
**AC-I (no age) describes Tier 3 cases that fulfill all AC-I criteria except “At least 1 of the cancers diagnosed before age 50”.
AC – Amsterdam criteria, MSI – microsatellite instability, MSS – microsatellite stable, MSI-H – highly microsatellite unstable, FDR – first degree relative, SDR – second degree relative, ACMG – American College of Medical Genetics.