TABLE 2.
Pathogenic and likely pathogenic variants.
| Family ID (pt.ID) | Gene | Transcript variant | Protein variant | Cancer localization and adenomas (age) | Family history1 |
| High risk variants | |||||
| 14 (14;16 and 14;20) | APC | c.289G>A | p.(Gly97Arg) | 14;16: Duodenal cancer (78), IHC = n/a. >100 colonic adenomas. 14;20: Transverse colon cancer (46), IHC = n/a. 25 colonic adenomas. |
Sister A+: Four primary colon cancers (57), <10 colonic adenomas and a hepatic mucinous cystadenocarcinoma (69). Also had Caroli disease. Sister B?: Breast cancer (55). Mother?: Colon cancer (66). Mat. 2DR?: Testicular cancer (68). |
| 165 (165;10) | MSH2 | c.2168C>T | p.(Ser723Phe) | Ascending colon cancer (47), IHC = MSH2 absent. Cancer in the major duodenal papilla (51), IHC = MLH1/PMS2 absent (MLH1 promoter methylation analysis showed methylation). 2 advanced adenomas. | Daughter+: Rectal cancer (25), 2 advanced, colonic adenomas. Mother–: Transverse colon cancer (44) and 1 advanced, colonic adenoma. Mat. 2/3DR–: Several cases of CRC (58–80). |
| 309 (309;10) | PMS2 | c.736_741delins TGTGTGTGAAG |
p.(Pro246Cysfs*3) | Cecal cancer (29), IHC = PMS2 absent. | Mother?: Breast cancer (68), endometrial cancer (73) and one advanced TA. Pat. 2DR?: Cervical cancer (50) |
| 409 (409;10) | PMS2 | 2275+1G>C | p.(?) | Ascending colon cancer (36), IHC = PMS2 absent. | No cancers in first degree relatives. |
| 27 (27;10) | POLE | c.1089C>A | p.(Asn363Lys) | Ascending colon cancer (28), IHC = Intact. Synchronous colorectal cancer (40). | Mother–: Malignant melanoma (68) and lung cancer (84). Father–: Colon cancer (67). Pat. 2DR–: Sigmoid colon cancer (50) |
| Moderate or low risk variants | |||||
| 6(6;142) | APC | c.3920T>A | p.(Ile1307Lys) | Sigmoid colon cancer (47), IHC = Intact. | Mother?: Died <40 years old (non-malignant disease) Father?: Not CRC. Pat. 2-4DR: Four CRCs (61–81)?; Sigmoid colon cancer (58) –; Synchronous ovarian cancer and colon cancer (50)? |
| 12 (12;82) | CHEK2 | c.1100delC | p.(Thr367Metfs15*) | Transverse colon cancer (66), IHC = MLH1/PMS2 absent (MLH1 promoter methylation analysis showed methylation). | Son?: Rectal cancer (42). Siblings?: Sigmoid colon cancer (46) and lung cancer (50); 3 advanced adenomas. |
| 200 (200;10) | CHEK2 | c.1100delC | p.(Thr367Metfs15*) | Colon cancer (36), IHC = MSH6 absent. | Not CRC in first degree relatives. |
| 55 (55;8) | EXO1 | c.2212-1G>C | p.(?) | Sigmoid colon (65), IHC = Intact. | Daughter+: Descending colon cancer (36). Father?: Sigmoid colon (76). |
| 397 (397;10) |
EXO1
MUTYH |
c.2212-1G>C c.536A>G |
p.(?) p.(Tyr179Cys) |
Rectal cancer (31), IHC = n/a. | Parents?: Not CRC. Pat. 2DR?: Leukemia (64). |
| 112 (112;80) | GALNT12 | c.907G>A | p.(Asp303Asn) | Rectal cancer (57), IHC = Intact. | Father?: Colon cancer (66). Brother?: Colon sigmoid cancer (50). Pat. 2DRs?: Prostate cancer (78), melanoma (83), rectal cancer (84) and 7 adenomas; Ovarian cancer (76) and bladder cancer 79. |
| 329 (329;10) | MUTYH | c.536A>G | p.(Tyr179Cys) | Ascending colon cancer (33), IHC = Intact. | No cancers in first- or second-degree relatives. |
| Variants with unknown risk (monoallelic pathogenic variants) | |||||
| 84 (84;14) | MSH3 | c.2319-1G>A | p.(?) | Sigmoid colon cancer (47), IHC = n/a. | Father?: Rectal cancer (76). Pat. 2-4DR?: Rectal cancer (58) and appendix cancer (58); Rectal cancer (55) and lung cancer (62); Rectal cancer (54); Breast cancer (49). |
| 136 (136;12) | NTHL1 | c.268C>T | p.(Gln90*) | Sigmoid colon cancer (49), IHC = Intact. Basal cell carcinoma (51), two adenomas. |
Father?: Colon cancer (81). Pat. 2DRs?: Breast cancer (62); Breast cancer (67); Colon cancer (61) and 3 adenomas Mat. 2DR?: Breast (71). |
1Family history includes verified cases of cancers and advanced colonic adenomas (villous morphology, size > 10 mm. or high-grade dysplasia) in first- and second-degree relatives. Single cases of basal cell skin cancer are not listed. Family members are separated by semicolons. TA, tubular adenoma; LG, low grade dysplasia; Mat, maternal; Pat., paternal; 2DR/3DR/4DR, second/third/fourth-degree relatives. Carrier status: ? Variant status unknown, + carrier, – non-carrier. IHC, immunohistochemical analysis; n/a, not available.