Table 1.
uFCRC Patient High Quality Variants, DSB Phenotypes, Polyp Histories, and Family Histories.
| Patient ID # |
HQ Variants | γH2AX + | Flow Cytometry |
Polyps (No or type) |
Family History of Neoplasia |
|---|---|---|---|---|---|
| 111797 | CHAF1B | Aph, UV | ↑S | No | Sis/CRC@41; M/CRC@72; MA/Ovar@63; MGF/Gastric@46; MGM/Panc@72 |
| 118294 | SHPRH | Aph, Campt | ↑S | No | F/pols@72; M/ut@71; M/BCC@76; MC/Laryn@51; MGF/Panc@69; PA/Br&Skin@33; PGF/Esoph@51 |
| 120713 (Pt1) | WRN; ERCC6 | No RX, Aph, Campt, UV, Etop | ↑G2/M | No | F/Blad; F&M/BCC@40s; Bro/BCC@50; Sis/CRC@48; PC1xR/Br@50; PC1xR/Ovar@40s |
| 122517 | POLD1; MCM10; MPG; SKA1 | Aph, Campt | Nl | mult | Sis/pols@37; F/CRC@41; PA/CRC@27; PGM/CRC@62; PGF/IntestSarc@31; PGF Sis/Sig@62 |
| 123000 | SPAG5 BRD4 | Aph, UV | NT | No | Bro/pols@64; Bro/pols@67; MU/CRC@60s; MA/CRC@60s; MC/CRC@68; F/CRC@79 |
| 123006 | MASTL | UV | ↑S | No | No |
| 123163 | DYNC1H1 CHAF1A | Nl | Nl | No | MA/Melan@45; A/Br@61; A/CRC@49; A/pols@58; Neph/pols@33; GM/CRC@63; GA/lymph@73; 4 1stCs1xR/CRC; GA/Uter@52; GA/Br@80,CRC; C/CRC@55 |
| 123320 | MSH2 | UV | ↑G2/M | No | No |
| 124744 | FANCL | Nl | Nl | No | Sis/pols@51; Bro/pols@56; Sis/pols@41; Sis/pol@39; Bro/pols@36; N/pols@27; M/Adeno@67; MA/CRC@51,pols@56; MGF/pols@47; F/CRC in pols@56; PA/CRC&pols@47; PC/CRC@58 |
| 125380 | [POLK]* | No Rx, Aph, UV | ↑S, G2/M | No | MGA/Esoph; MGA/Gastric; MCA/CRC; F/Pros@63; F/pols@67; F/Panc@70; PU/pols |
| 125659 | EEPD1 | UV | Nl | No | M/pol@70s; MU/Panc@53; PGF/GI@89; PGM/Liver@63 |
| 126780 | ERCC2 | No Rx, Aph | Nl | No | M/Panc@60; MU/Gastric@60; MU/unknown@50; F/CRC@60; F/pols |
| 126875 | ANAPC10 | No Rx, Aph | Aph: ↓S ↑G2/M | No | S/Bileduct@41, MU/CRC@50s; PU/CRC@50s; MSH2 mutation in PA/Gastric@60s; pt – for MSH2 |
| 127581 | CTC1 | No Rx, Aph | Aph: ↑G2/M | No | M/CRC@58; PGF/CRC@58 |
| 129338 | None | Nl | ↑S, G2/M | mult@50s | MU/pols&CRC@79; Son/Blad@50s; Son/pols@50s; MU/pols@75; MC/Br@43; MU/pols&CRC@63; MC/pols@60s; MA/pols@75; MGM/Panc@65; MA/CRC@60s&Endom&Ovar; Son/CRC |
| 132231 | C19Orf40 | Nl | Nl | 2 adv | Bro/pols@50 |
| 132406 | DDX11*; LIG1; | Aph, UV | NT | 1 ser | Bro/CRC&pols@40,55; M/pols@50s&CRC@72 |
| 132667 | LIG3 | Aph, UV | NT | >5 serr adv@<50 | Bro/CRC@44; MU/Canc@70s; MU/Stom/Esopha@50s, MA/Panc@70s; MC/Brain@57; MC/CRC@45; MC/CRC@52; MU/Canc@85; MC/Lung@52 |
| 133012 | POLD3 | No Rx, Aph | Nl | 3 adv | M/pols@60s; P1/2Sis/pols@32; PU/pols@50 |
| 134321 | None | Nl | Nl | 1 adv | NA |
HQ Variant: variant with GO annotation of DNA replication, DNA repair, checkpoint, mitotic, or mitosis; reported in < 1/100 exomes; and scoring > 0.95 on the current PolyPhen2 program and (+) by 2/3: SIFT, Provean, and MutationAssessor programs. γH2AX+: conditions under which the patient's cells showed statistically greater staining than the control or controls: 1) higher than the optimized discriminator line for aphidicolin or UV treatment (Fig 2); 2) higher than all controls for the No Rx condition; or 3) statistically greater than its specific matched controls (Pt1 and Pt2). Flow Cytometry: replicative phases in which the % of patient’s cells was > 20% higher than the controls. Polyps: polyps in the patients - known number and nature are listed (mult: >3, adv: advanced (> 1 cm, high grade dysplasia, or villous histology), ser: serrated adenomas. NT: not tested, Nl: normal. Family history of neoplasia: F: father, M: mother, Sis: sister, Bro: brother, MA: maternal aunt, MU: maternal uncle, PU: paternal uncle, MC: maternal cousin etc./organ site@age at diagnosis, Pols: polyps.
The POLK variant was predicted to be dysfunctional by PP2 and MutationAssessor but narrowly not by SIFT, and hence is technically not HQV (see main text).
The DDX11 variant sequence was also found in 2 other strong homology regions on chr12 and was flagged with low quality metrics in ExAC.