Table 3.
Early-onset patients with a second pathogenic variant or variant of unknown significance in a gastrointestinal cancer susceptibility gene.
| Age at cancer onset (years) | Cancer | MMR pathogenic variant | Number of additional PV | Additional PV | Number of VUS | VUS |
|---|---|---|---|---|---|---|
| 21 | Colorectal cancer | MLH1(NM_000249.3):c.199 G > T, p.(Gly67Trp) | 1 | EPCAM whole gene deletion including 3ʹUTR | 1 | NBN(NM_002485.5):c.939 G > A, p.(Ala313Ala) |
| 28 | Colorectal cancer | PMS2 gene conversion. | 1 | MUTYH(NM_001048171.1):c.1145 G > A, p.(Gly382Asp)a | ||
| 26 | Colorectal cancer | Deletion of PMS2 exons 9 to 10. | 1 | MUTYH(NM_001048171.1): c.1145 G > A, p.(Gly382Asp)a | 1 | ATM(NM_000051.3):c.4802 G > A, p.(Ser1601Asn) |
| 25 | Colorectal cancer | MSH2(NM_000251.2):c.2152 C > T, p.(Gln718*) | 1 | Duplication of BMPR1A exons 3 to 13. | ||
| 26 | Colorectal cancer | MLH1(NM_000249.3):c.1909delA, p.(Ile637Leufs*6) | 1 | MSH2(NM_000251.2):c.1413 A > C, p.(Lys471Asn) | ||
| 29 | Colorectal cancer | MLH1 hypermethylation. | 2 | APC(NM_000038.5):c.6136 G > A, p.(Ala2046Thr); ATM(NM_000051.3):c.9169 T > G, p.(*3057Glyext*29) | ||
| 30 | Colorectal cancer | MLH1(NM_000249.3):c.454-2 A > G, p.(?) | 3 | ATM(NM_000051.3):c.6795 C > T, p.(Phe2265Phe); ATM(NM_000051.3):c.1250 C > A, p.(Thr417Asn); MSH6(NM_000179.2):c.984 C > T, p.(Ser328Ser) | ||
| 30 | Colorectal cancer | MLH1(NM_000249.3):c.769del, p.(Ile257Serfs*11) | 1 | MSH2(NM_000251.2):c.832 G > A, p.(Glu278Lys) | ||
| 16 | Colorectal cancer | MSH2(NM_000251.2):c.2038 C > T, p.(Arg680*) | 1 | POLD1(NM_001256849.1):c.355 C > T, p.(Arg119Cys) | ||
| 17 | Duodenal cancer | PMS2(NM_000535.5):c.989-2 A > G, p.(?) | 3 | POLE(NM_006231.4):c.895 A > G, p.(Met299Val); MUTYH(NM_001048171.1):c.1584 C > T, p.(His528His)a; MUTYH(NM_001048171.1):c.567 T > C, p.(Arg189Arg)a | ||
| 19 | Colorectal cancer | MSH2(NM_000251.2):c.942 + 3 A > T, p.(Ala266Valfs*16) | 1 | POLE(NM_006231.4):c.5627 A > G, p.(Lys1876Arg) | ||
| 28 | Colorectal cancer | MSH2(NM_000251.2):c.1662_1759del, p.(Ser554Argfs*11) | 1 | POLE(NM_006231.4):c.6286 C > G, p.(Leu2069Val) | ||
| 22 | Glioblastoma | Deletion of exons 9 and 10 of MSH2. | 1 | POLD1(NM_001256849.1):c.961 G > A, p.(Gly321Ser) | ||
| 23 | Glioblastoma | MSH2(NM_000251.2):c.970 C > T, p.(Gln324*) | 3 | BRIP1(NM_032043.3):c.2564 G > A, p.(Arg855His); CHEK2(NM_007194.4):c.1009-5 T > C, p.(?); POLE(NM_006231.4):c.6454 G > A, p.(Val2152Met) | ||
| 30 | Glioblastoma | MLH1(NM_000249.3):c.949del, p.(Leu317Cysfs*50) | 0 | 1 | POLE(NM_006231.4):c.3757 G > C, p.(Glu1253Gln) | |
| 22 | Colorectal cancer | MLH1(NM_000249.3):c.785_787del, p.(Ile262del) | 1 | MLH1(NM_000249.3):c.347 C > A, p.(Thr116Lys) | ||
| 28 | Colorectal cancer | MSH2(NM_000251.2):c.942 + 3 A > T, p.(Val265_Gln314del), p.(Ala266Valfs*16) | 2 | MLH1(NM_000249.3):c.1317 A > C, p.(Glu439Asp); POLD1(NM_001256849.1):c.1867C > T, p.(Arg623Trp) | ||
| 28 | Colorectal cancer | MLH1(NM_000249.3):c.678-2 A > T, p.(?) | 1 | ATM(NM_000051.3):c.6100 C > T, p.(Arg2034*) | 1 | APC(NM_000038.5):c.7757 G > T, p.(Ser2586Ile) |
| 24 | Colorectal cancer | Deletion of MSH2 exon 3. | 1 | POLD1(NM_001256849.1):c.455 C > T,p.(Ala152Val) | ||
| 29 | Colorectal cancer | MSH6(NM_000179.2):c.3261dup, p.(Phe1088Leufs*5) | 1 | MUTYH(NM_001128425):c.1477 G > T, p.(Val493Phe)a | ||
| 16 | Colorectal cancer | MSH2(NM_000251.2):c.478_479del, p.(Gln160Glyfs*17) | 2 | BRCA1(NM_007294.4):c.5123 C > T, p.(Ala1708Val); POLE(NM_006231.4):c.2089 C > G, p.(Pro697Ala) | ||
| 27 | Colorectal cancer | MSH6(NM_000179.2):c.2234 T > A, p.(Ile745Asn) | 2 | CDH1(NM_004360.5):c.2603 G > A, p.(Arg868His); NTHL1(NM_002528.7):c.494 G > A, p.(Gly165Asp) | ||
| 29 | Colorectal cancer | MLH1 hypermethylation. | 1 | APC(NM_000038.5):c.6682 G > A, p.(Val2228Ile) |
MMR mismatch-repair, PV pathogenic variant, VUS variant of unknown significance.
aHeterozygous.