Table 1

Variant calling of germline variants in CTNNA1, MAP3K6 and MYD88 in patients with GC

Patient IDHDGC/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 changeAmino acid changeMAF ExAC§PhyloPAlign GVGD¶SIFT**PolyPhen††
270AHDGCDGC (62 M)DGC: 1 (63); GC: 2 (54, 71)GC: 4 (45, 51, 57, 72)BRAT (49) CTNNA1 c.80_81delp.Arg27fs§§0N/AN/AN/AN/A
162A‡‡HDGCDGC (33 M)IGC: 1 (42)ES (69) CTNNA1 c.536C>Tp.Ala179Val0.0011794.16C0Tol.Benign
528AOtherGC (42 F)DC (56) CTNNA1 c.536C>Tp.Ala179Val0.0011794.16C0Tol.Benign
240AHDGCDGC (54 F)IGC: 1 (80)GC: 2 (73, 81)PrCa (71); CRC (78) CTNNA1 c.618G>Cp.Gln206His0.0045170.85C0Tol.Pos. D.
380AHDGCDGC (36 F)Leu (37) CTNNA1 c.770A>Gp.Asn257Ser0.00051894.89C0Tol.Benign
432AHDGCDGC (40 F)GC: 1 (56) CTNNA1 c.964_988dupp.Arg330fs0N/AN/AN/AN/A
746AHDGCDGC (30 F)GC: 1 (48)Leu (?) CTNNA1 c.1328dupp.Asn443fs0N/AN/AN/AN/A
233AHDGCDGC (41 F)GC: 1 MAP3K6 c.598G>Tp.Asp200Tyr0.0029535.29C65Del.Prob. D.
250AFGCIGC (62 M)IGC: 1 (54); GC: 1 (48)GC: 1 (80) MAP3K6 c.598G>Tp.Asp200Tyr0.0029535.29C65Del.Prob. D.
183AOtherGC (39 F) MAP3K6 c.1001C>Tp.Ala334Val0.000025315.21C65Del.Pos. D.
295AFGCIGC (62 M)GC: 1 (61)GC: 1 (78)BRAT (85); CUP (60, 75); CRC (77, 84) MAP3K6 c.1256-2A>Gp.?0.003761N/AN/AN/AN/A
757AHDGCDGC (38 M) MAP3K6 c.1256-2A>Gp.?0.003761N/AN/AN/AN/A
709AOtherGC (40 M) MAP3K6 c.1622T>Cp.Leu541Pro02.06C65Del.Pos. D.
167A‡‡HDGCDGC (31 F)BC (59); MM (60) MAP3K6 c.1772A>Gp.Tyr591Cys§§02.71C65Del.Benign
737AFGCIGC (66 M)GC: 1 (86)GC: 1 (60) MAP3K6 c.2837C>Tp.Pro946Leu0.0052963.35C65Del.Prob. D.
770AHDGCDGC (48 M)GC (51)PrCa (71) MAP3K6 c.2837C>Tp.Pro946Leu0.0052963.35C65Del.Prob. D.
729A‡‡FIGCIGC (48 F)GC: 2 (40, 79) MAP3K6 c.2837C>Tp.Pro946Leu0.0052963.35C65Del.Prob. D.
132AHDGCDGC (44 F)DGC: 1 (34)Leu (62) MAP3K6 c.2954C>Tp.Pro985Leu0.00097743.43C65Del.Pos. D.
108AFGCIGC (68 M)DGC: 1 (22); GC: 1 (78)CRC (50, 59) MAP3K6 c.2954C>Tp.Pro985Leu0.00097743.43C65Del.Pos. D.
210AOtherDGC (40 F) MAP3K6 c.3070A>Gp.Lys1024Glu0.004362−0.6C0Tol.Benign
244AHDGCDGC (26 M)LiC (55) MAP3K6 c.3070A>Gp.Lys1024Glu0.004362−0.6C0Tol.Benign
166AHDGCDGC (66 F)GC: 1 (48)GC: 1 (60)BC (60); PC (48, 60); PrCa (71); LC (53, 55); CRC (?); RC (53) MAP3K6 c.3143A>Gp.His1048Arg0.00021131.09C25Del.Benign
183AEOGCGC (39 F) MAP3K6 c.3181G>Ap.Ala1061Thr0.00079991.34C0Tol.Benign
113BFGCIGC (72 F)IGC: 1 (82); GC: 3 (63, 66, 82)HL (72) MAP3K6 c.3481C>Gp.Pro1161Ala0.000016840.61C0Tol.Benign
753AHDGCDGC (32 M) MAP3K6 c.3562C>Tp.Gln1188*0.00001682N/AN/AN/AN/A
270AHDGCDGC (62 M)DGC: 1 (63); GC: 2 (54, 71)GC: 4 (45, 51, 57, 72)BRAT (49) MYD88 c.251C>Tp.Thr84Ile01.66C0Tol.Prob. D.
537AOtherGC (41) MYD88 c.518G>Ap.Arg173His0.00002477−0.04C0Tol.Benign
036A‡‡HDGCDGC (23)BC (45, 45); EC (70) MYD88 c.712C>Tp.Arg238Cys§§03.76C15Del.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