Variant calling of germline variants in CTNNA1, MAP3K6 and MYD88 in patients with GC
| Patient ID | HDGC/FIGC/FGC/ EOGC/other* | Diagnosis index (age and gender) | GC in first-degree relatives, n (age) | GC in second-degree relatives, n (age) | Other cancer diagnoses in first-degree and second-degree relatives (age)† | Gene‡ | Nucleotide change | Amino acid change | MAF ExAC§ | PhyloP | Align GVGD¶ | SIFT** | PolyPhen†† |
| 270A | HDGC | DGC (62 M) | DGC: 1 (63); GC: 2 (54, 71) | GC: 4 (45, 51, 57, 72) | BRAT (49) | CTNNA1 | c.80_81del | p.Arg27fs§§ | 0 | N/A | N/A | N/A | N/A |
| 162A‡‡ | HDGC | DGC (33 M) | IGC: 1 (42) | ES (69) | CTNNA1 | c.536C>T | p.Ala179Val | 0.001179 | 4.16 | C0 | Tol. | Benign | |
| 528A | Other | GC (42 F) | DC (56) | CTNNA1 | c.536C>T | p.Ala179Val | 0.001179 | 4.16 | C0 | Tol. | Benign | ||
| 240A | HDGC | DGC (54 F) | IGC: 1 (80) | GC: 2 (73, 81) | PrCa (71); CRC (78) | CTNNA1 | c.618G>C | p.Gln206His | 0.004517 | 0.85 | C0 | Tol. | Pos. D. |
| 380A | HDGC | DGC (36 F) | Leu (37) | CTNNA1 | c.770A>G | p.Asn257Ser | 0.0005189 | 4.89 | C0 | Tol. | Benign | ||
| 432A | HDGC | DGC (40 F) | GC: 1 (56) | CTNNA1 | c.964_988dup | p.Arg330fs | 0 | N/A | N/A | N/A | N/A | ||
| 746A | HDGC | DGC (30 F) | GC: 1 (48) | Leu (?) | CTNNA1 | c.1328dup | p.Asn443fs | 0 | N/A | N/A | N/A | N/A | |
| 233A | HDGC | DGC (41 F) | GC: 1 | MAP3K6 | c.598G>T | p.Asp200Tyr | 0.002953 | 5.29 | C65 | Del. | Prob. D. | ||
| 250A | FGC | IGC (62 M) | IGC: 1 (54); GC: 1 (48) | GC: 1 (80) | MAP3K6 | c.598G>T | p.Asp200Tyr | 0.002953 | 5.29 | C65 | Del. | Prob. D. | |
| 183A | Other | GC (39 F) | MAP3K6 | c.1001C>T | p.Ala334Val | 0.00002531 | 5.21 | C65 | Del. | Pos. D. | |||
| 295A | FGC | IGC (62 M) | GC: 1 (61) | GC: 1 (78) | BRAT (85); CUP (60, 75); CRC (77, 84) | MAP3K6 | c.1256-2A>G | p.? | 0.003761 | N/A | N/A | N/A | N/A |
| 757A | HDGC | DGC (38 M) | MAP3K6 | c.1256-2A>G | p.? | 0.003761 | N/A | N/A | N/A | N/A | |||
| 709A | Other | GC (40 M) | MAP3K6 | c.1622T>C | p.Leu541Pro | 0 | 2.06 | C65 | Del. | Pos. D. | |||
| 167A‡‡ | HDGC | DGC (31 F) | BC (59); MM (60) | MAP3K6 | c.1772A>G | p.Tyr591Cys§§ | 0 | 2.71 | C65 | Del. | Benign | ||
| 737A | FGC | IGC (66 M) | GC: 1 (86) | GC: 1 (60) | MAP3K6 | c.2837C>T | p.Pro946Leu | 0.005296 | 3.35 | C65 | Del. | Prob. D. | |
| 770A | HDGC | DGC (48 M) | GC (51) | PrCa (71) | MAP3K6 | c.2837C>T | p.Pro946Leu | 0.005296 | 3.35 | C65 | Del. | Prob. D. | |
| 729A‡‡ | FIGC | IGC (48 F) | GC: 2 (40, 79) | MAP3K6 | c.2837C>T | p.Pro946Leu | 0.005296 | 3.35 | C65 | Del. | Prob. D. | ||
| 132A | HDGC | DGC (44 F) | DGC: 1 (34) | Leu (62) | MAP3K6 | c.2954C>T | p.Pro985Leu | 0.0009774 | 3.43 | C65 | Del. | Pos. D. | |
| 108A | FGC | IGC (68 M) | DGC: 1 (22); GC: 1 (78) | CRC (50, 59) | MAP3K6 | c.2954C>T | p.Pro985Leu | 0.0009774 | 3.43 | C65 | Del. | Pos. D. | |
| 210A | Other | DGC (40 F) | MAP3K6 | c.3070A>G | p.Lys1024Glu | 0.004362 | −0.6 | C0 | Tol. | Benign | |||
| 244A | HDGC | DGC (26 M) | LiC (55) | MAP3K6 | c.3070A>G | p.Lys1024Glu | 0.004362 | −0.6 | C0 | Tol. | Benign | ||
| 166A | HDGC | DGC (66 F) | GC: 1 (48) | GC: 1 (60) | BC (60); PC (48, 60); PrCa (71); LC (53, 55); CRC (?); RC (53) | MAP3K6 | c.3143A>G | p.His1048Arg | 0.0002113 | 1.09 | C25 | Del. | Benign |
| 183A | EOGC | GC (39 F) | MAP3K6 | c.3181G>A | p.Ala1061Thr | 0.0007999 | 1.34 | C0 | Tol. | Benign | |||
| 113B | FGC | IGC (72 F) | IGC: 1 (82); GC: 3 (63, 66, 82) | HL (72) | MAP3K6 | c.3481C>G | p.Pro1161Ala | 0.00001684 | 0.61 | C0 | Tol. | Benign | |
| 753A | HDGC | DGC (32 M) | MAP3K6 | c.3562C>T | p.Gln1188* | 0.00001682 | N/A | N/A | N/A | N/A | |||
| 270A | HDGC | DGC (62 M) | DGC: 1 (63); GC: 2 (54, 71) | GC: 4 (45, 51, 57, 72) | BRAT (49) | MYD88 | c.251C>T | p.Thr84Ile | 0 | 1.66 | C0 | Tol. | Prob. D. |
| 537A | Other | GC (41) | MYD88 | c.518G>A | p.Arg173His | 0.00002477 | −0.04 | C0 | Tol. | Benign | |||
| 036A‡‡ | HDGC | DGC (23) | BC (45, 45); EC (70) | MYD88 | c.712C>T | p.Arg238Cys§§ | 0 | 3.76 | C15 | Del. | Pos. D. |
N/A, not available; (?), age is not known.
*EOGC, early-onset gastric cancer; FGC, familial gastric cancer; FIGC, familial intestinal gastric cancer; HDGC, hereditary diffuse gastric cancer. For details on these categories, see online supplementary file 2.
†BC, breast cancer; BRAT, brain tumour; CRC, colorectal cancer; CUP, cancer of unknown primary; DC, duodenal cancer; DGC, diffuse-type gastric cancer; EC, endometrial cancer; ES, oesophageal cancer; GC, gastric cancer; HL, Hodgkin lymphoma; IGC, intestinal-type gastric cancer; LC, lung cancer; Leu, leukaemia; LiC, liver cancer; MM, malignant melanoma; PC, pancreatic cancer; PrCa, prostate cancer; RC, renal cancer.
‡NM_001903.2 (CTNNA1), NM_004672.4 (MAP3K6) and NM_001172567.1 (MYD88).
§Minor allele frequency (MAF) of the corresponding variant in the Exome Aggregation Consortium (ExAC) database (see Materials and methods).
¶ GVGD, Grantham Variation Grantham Difference score. Class score; C0 is considered benign.
** SIFT, Sorting Intolerant from Tolerant; Del., deleterious; Tol., tolerated.
††Pos. D., possibly damaging; Prob. D., probably damaging.
‡‡ Whole exome sequencing (WES) has been performed on germline DNA derived from these individuals prior to this study.12
§§Variant has previously been reported in other studies.9 11 12