Table 1.
Late onset CMMRD patients with first cancer diagnosis at age ≥ 25 years
| Publication | Patient ID | Gene (Transcript ID) | Variant 1 | Variant 2 | Cancer Diagnoses (age in years) - Molecular Pathology | Other Clinical Features (age in years) |
|---|---|---|---|---|---|---|
| Present study | Case 1 |
MSH6 (NM_000197.3) |
c.3226C>T p.(Arg1076Cys) missense |
c.3226C>T p.(Arg1076Cys) missense |
OC (27) EC (27) OC relapse (31) CRC (43) - absent MSH6 expression, MSI-high CRC (52) - irregular MSH6 expression GBM (56) - IDH-WT, MSS, TMB 368mut/Mb, POLE variants |
Duodenal and colorectal adenomas and polyps (39 + ) Duodenal adenoma (53) - irregular MSH6 expression, MSS LS family history |
| Case 2 |
MLH1 |
c.306G>A a p.[(Lys70_Glu102del,Glu102=)] loss of 33 AA, silent |
c.306G>A a p.[(Lys70_Glu102del,Glu102=)] loss of 33 AA, silent |
EC (38) - present MMR expression, MSI-high |
Three colonic adenomas (39) Three affected siblings with either GC (35), BT (30), or GIC (35) |
|
| Gardès et al. 38 | P3 |
MSH6 (NM_000197.3) |
c.3226C>T p.(Arg1076Cys) missense |
c.3226C>T p.(Arg1076Cys) missense |
CRC (45) CRC (49) |
Colorectal polyps (age not reported) |
| Lavoine et al. 39 | 11(15) |
PMS2 |
c.2531C>A p.(Pro844His) missense |
c.2531C>A p.(Pro844His) missense |
CRC (33) - MSI-high CRC (46)b |
Two colonic adenomas (33) Sibling with CRC (20), GC (32), and GBM (32) |
| Li et al. 40 c | III-3 |
PMS2 |
c.2002A>G a p.[(Ile668*,Ile668Val)] truncating, missense |
c.2002A>G a p.[(Ile668*,Ile668Val)] truncating, missense |
CRC (26) - absent PMS2 expression DC (40) |
Gastrointestinal polyps (age not reported) LS family history CALM Absent PMS2 expression in normal tissue |
| NA |
PMS2 |
c.2002A>G a p.[(Ile668*,Ile668Val)] truncating, missense |
c.2002A>G a p.[(Ile668*,Ile668Val)] truncating, missense |
CRC (38) | None reported | |
| NA |
PMS2 |
c.2002A>G a p.[(Ile668*,Ile668Val)] truncating, missense |
c.2002A>G a p.[(Ile668*,Ile668Val)] truncating, missense |
CRC (31) | None reported | |
| NA |
PMS2 |
c.2002A>G a p.[(Ile668*,Ile668Val)] truncating, missense |
c.2002A>G a p.[(Ile668*,Ile668Val)] truncating, missense |
CRC (31) | None reported | |
| Shuen et al. 41 | MMR108 |
PMS2 |
c.2531C>A p.(Pro844His) missense |
c.1261C>T p.(Arg421*) truncating |
CRC (27) CRC (27) |
Four colorectal adenomas (27) Absent PMS2 expression in normal tissue |
| MMR120 |
MSH6 (NM_000197.3) |
c.3226C>T p.(Arg1076Cys) missense |
c.1421_1422dupTG p.(Gln475Glyfs*7) truncating |
GBM (27) GBM relapse (28) |
None reported | |
| MMR189 |
PMS2 |
c.137G>T p.(Ser46Ile) missense |
c.137G>T p.(Ser46Ile) missense |
CRC (28) CRC (32) M (45) BC (49) CRC (50) CRC (52) PrC (53) |
Absent PMS2 expression in normal tissue | |
| Xie et al. 42 | III.1 |
MSH6 (NM_000197.3) |
c.3226C>T p.(Arg1076Cys) missense |
c.3226C>T p.(Arg1076Cys) missense |
CRC (32) - subclonal absent MSH6 expression, MSS, TMB-high CRC relapse (34) |
Neurofibromas (unknown) Fourth degree consanguineous parents LS family history CALM |
| Bruekner et al. 43 | NA |
MSH2 |
c.188T>A p.(Val63Glu) missense |
c.188T>A p.(Val63Glu) missense |
CRC (25) | Two siblings with CRC (17 and 26) |
AA amino acid, CALM cafe au lait macule, CMMRD constitutional mismatch repair deficiency, LS Lynch syndrome, MSI microsatellite instability, MSS microsatellite stable, TMB tumour mutation burden, BC bladder cancer, BT brain tumour (unknown classification), CRC colorectal cancer, DC duodenal cancer, EC endometrial cancer, GBM glioblastoma (astrocytoma), GC gastric cancer, GIC gastrointestinal cancer (unknown location), HGG high grade glioma (including primitive neuroectodermal tumour), IC intestinal cancer (assumed jenunal or ileal), M melanoma, OC ovarian cancer, PrC prostate cancer.
aThe variant causes a “leaky” splice effect.
bA rectal cancer diagnosed at age 46 years was previously unreported.
c Also see Biswas et al.45 for functional analyses of PMS2 c.2002A>G.