Background
Methods
Ethics statement
Patient selection
South American Institutions | Total number of patients/families | MMR mutation carriers | % of MMR mutation carriers | Mean age at CRC diagnosis | Mean age at endometrial cancer diagnosis |
---|---|---|---|---|---|
Hospital Italiano (Buenos Aires, Argentina) | 28 | 14 | 50.0 | 44.3 (SD 6.2) | 46.3 (SD 5.5) |
Hospital de las Fuerzas Armadas (Montevideo, Uruguay) | 25 | 7 | 28.0 | 35.1 (SD 7.6) | 41.5 (SD 8.3) |
Clinica Las Condesa (Santiago, Chile) | 50 | 20 | 40.0 | 35.7 (SD 10.7) | 41.1 (SD 8.8) |
Barretos Cancer Hospitala (Barretos, Brazil) | 23 | 15 | 65.2 | 39.4 (SD 13.8) | 49.8 (SD 5.3) |
Colombiac
| 13 | 8 | 61.5 | NA | NA |
Southeastern Brazilb
| 128 | 35 | 27.3 | 42.3 (SD 11.4) | 48.8 (SD 2.4) |
Total
| 267 | 99 | 37.1 |
Disease-predisposing mutations
Mutation nomenclature
Variants of uncertain significance
Statistical analysis
Results
Gene | Nucleotide | Consequence | Exon | Reported as | Country | Number of families | References |
---|---|---|---|---|---|---|---|
MLH1
| c.1-?_116 + ?del | p.M1_C39 > FfsX13 | 1 | Causal | Chile | 2 | InSIGHT |
c.199G > A | p.G67R | 2 | Causal | Argentina | 1 | InSIGHT | |
c.211G > T | p.E71X | 3 | Causal | Brazil | 1 | InSIGHT | |
c.289 T > G | p.Y97D | 3 | VUS | Uruguay | 1 | InSIGHT | |
C.336 T > A | p.H112Q | 4 | VUS | Argentina | 1 | InSIGHT | |
c.350C > T | p.T117M | 4 | Causal | Uruguay | 2 | InSIGHT | |
c.421C > G | p.P141A | 5 | VUS | Colombia | 1 | Giraldo et al. 2005 [2] | |
c.503dupA | p.N168KfsX4 | 6 | Causal | Chile | 1 | InSIGHT | |
c.503delAa
| p.N168IfsX34 | 6 | Causal | Brazil | 1 | Not previously described | |
c.545 + 3A > G | 6 | Causal | Brazil | 2 | InSIGHT | ||
c.588 + 2 T > Aa
| 7 | Causal | Brazil | 1 | Valentin et al. 2011 [3] | ||
c.588 + 5G > C | 7 | Causal | Brazil | 1 | InSIGHT | ||
c.665delA | p.N222MfsX7 | 8 | Causal | Uruguay | 2 | InSIGHT | |
c.676C > T | p.R226X | 8 | Causal | Argentina | 1 | InSIGHT | |
c.677G > A | p.R226Q | 8 | Causal | Argentina, Brazil | 3 | InSIGHT | |
c.677 + 5G > A | 8 | Likely causal | Chile | 1 | French MMR network | ||
c.779 T > G | p.L260R | 9 | Causal | Brazil | 1 | InSIGHT | |
c.790 + 1G > A | 9 | Causal | Chile, Colombia | 3 | InSIGHT | ||
c.791-6_793delgtttagATCa
| 10 | Causal | Brazil | 1 | Valentin et al. 2011 [3] | ||
c.794G > C | p.R265P | 10 | VUS | Chile | 1 | InSIGHT | |
c.901C > T | p.Q301X | 11 | Causal | Chile | 1 | InSIGHT | |
c.1013A > Ga
| p.N338S | 11 | VUS | Brazil | 1 | InSIGHT | |
c.1038 + 1G > Ta
| p.Y347FfsX13 | 11 | Causal | Chile | 1 | Wielandt et al. 2012 | |
c.1039-8T_1558?896Tdupa
| p.520Vfs564X | 12 to 13 | Causal | Colombia | 2 | Alonso-Espinaco et al. 2011 [11] | |
c.1276C > T | p.Q426X | 12 | Causal | Brazil | 3 | InSIGHT | |
c.1459C > T | p.R487X | 13 | Causal | Brazil | 1 | InSIGHT | |
c.1499_1501delTCAa
| p.I500del | 13 | Causal | Brazil | 1 | Rossi et al. 2002 [5] | |
c.1558 + 1G > T | 13 | Causal | Brazil | 1 | InSIGHT | ||
c.1558 + 14G > A | 13 | VUS | Colombia | 2 | InSIGHT | ||
c.1559-2A > C | 13 | Causal | Chile | 1 | InSIGHT | ||
c.1559-?_1731 + ?del | p.V520_S577 > GfsX7b
| 14 -15 | Causal | Chile | 1 | Wielandt et al. 2012 | |
c.1639_1643dup TTATAa
| p.L549YfsX44 | 14 | Causal | Brazil | 1 | Valentin et al. 2011 [3] | |
c.1690_1693delCTCA | p.L564FfsX26 | 15 | Causal | Brazil | 1 | InSIGHT | |
c.1724G > A | p.R575K | 15 | VUS | Argentina | 1 | InSIGHT | |
c.1731 + 3A > Ta
| Skipping exon 15 | 15 | Causal | Chile | 1 | Alvarez et al. 2010 [6] | |
c.1846delAAG | p.K616del | 16 | Causal | Argentina | 1 | InSIGHT | |
c.1852_1853delinsGC | p.K618A | 16 | Causal | Argentina | 1 | InSIGHT | |
c.1852_1854 delAAG | p.K618del | 16 | Causal | Argentina | 1 | InSIGHT | |
c.1853A > C | p.K618T | 16 | VUS | Brazil | 1 | InSIGHT | |
c.1853delAinsTTCTTa
| p.K618IfsX4 | 16 | Causal | Brazil | 2 | Valentin et al. 2011 [3] | |
c.1856delGa
| 16 | Causal | Colombia | 2 | Giraldo et al. 2005 [2] | ||
c.1890dupa
| p.D631fsX1 | 16 | Causal | Argentina | 1 | Valentin et al. 2011 [3] | |
c.1897-?_1989 + ?dela
| 17-19 | Causal | Brazil | 1 | Not previously described | ||
c.1918C > T | p.P640T | 17 | VUS | Colombia | 1 | InSIGHT | |
c.1975C > T | p.R659X | 17 | Causal | Brazil | 1 | InSIGHT | |
c.1998G > A | p.W666X | 18 | Causal | Brazil | 1 | Rossi et al. 2012 [5] | |
c.2027 T > C | p.L676P | 18 | Causal | Brazil | 1 | InSIGHT | |
c.2041G > A | p.A681T | 18 | Likely causal | Chile, Brazil, Colombia | 4 | French MMR network | |
c.2092_2093delTC | p.S698RfsX5 | 18 | Causal | Chile | 1 | Alvarez et al. 2010 [6] | |
c.2224C > Ta
| p.Q742X | 19 | Causal | Brazil | 1 | Valentin et al. 2011 [3] | |
c.2252_2253dupAA | p.V752KfsX26 | 19 | VUS | Brazil | 1 | InSIGHT | |
c.2104-?_2271 + ?delb
| p.S702_X757del | 19 | Causal | Chile | 2 | Wielandt et al. 2012 | |
MSH2
| c.71delAa
| p.Q24fs | 1 | Causal | Brazil | 1 | Not previously described |
c.166G > Ta
| p.E56X | 1 | Causal | Argentina | 1 | InSIGHT | |
c.174dupCa
| 1 | Causal | Brazil | 1 | Not previously described | ||
c.175dupCa
| p.K59QfsX23 | 1 | Causal | Brazil | 1 | Valentin et al. 2011 [3] | |
c.181C > Ta
| p.Q61X | 1 | Causal | Uruguay | 1 | Sarroca et al. 2003 | |
c.187delG | p.V63fsX1 | 1 | Causal | Brazil | 1 | InSIGHT | |
c.289C > T | p.Q97X | 2 | Causal | Argentina | 1 | InSIGHT | |
c.212-?_366 + ?del | p.A72_K122 > FfsX9 | 2 | Causal | Chile | 1 | InSIGHT | |
c.388_389delCA | p.Q130VfsX2 | 3 | Causal | Brazil, Argentina | 2 | InSIGHT | |
c.530_531delAAa
| p.E177fsX3 | 3 | Causal | Uruguay | 1 | Sarroca et al. 2003 | |
c.596delTGa
| 3 | Causal | Colombia | 1 | Giraldo et al. 2005 [2] | ||
c.862C > T | p.Q287X | 5 | Causal | Brazil | 1 | InSIGHT | |
c.897 T > G | p.Y299X | 5 | Causal | Chile | 1 | Wielandt et al. 2012 | |
c.942 + 3 A > T | 5 | Causal | Brazil | 1 | InSIGHT | ||
c.1077-?_1276 + ?del | p.L360KfsX16 | 7 | Causal | Argentina | 1 | InSIGHT | |
c.1147C > T | p.R382X | 7 | Causal | Brazil | 1 | InSIGHT | |
c.1215C > A | p.Y405X | 7 | Causal | Chile | 1 | InSIGHT | |
c.1216C > T | p.R406X | 7 | Causal | Uruguay | 1 | InSIGHT | |
c.1249delG | p.V417LfsX21 | 7 | Causal | Brazil | 1 | InSIGHT | |
c.1255C > T | p.Q419X | 7 | Causal | Brazil | 1 | InSIGHT | |
c.1444A > Ta
| p.R482X | 9 | Causal | Brazil | 1 | Valentin et al. 2011 [3] | |
c.1447G > T | p.E483X | 9 | Causal | Brazil | 2 | InSIGHT | |
c.1667delTa
| p.L556X | 11 | Causal | Brazil | 1 | Valentin et al. 2011 [3] | |
c.1667_1668insAa
| p.T557DfsX5 | 11 | Causal | Brazil | 1 | Rossi et al. 2002 [5] | |
c.1910delCa
| p.R638GfsX47 | 12 | Causal | Argentina | 1 | Vaccaro et al. 2007 | |
c.1967_1970dupACTTa
| p.F657LfsX3 | 12 | Causal | Brazil | 1 | Valentin et al. 2011 [3] | |
c.2038C > T | p.R680X | 13 | Causal | Chile | 1 | InSIGHT | |
c.2046_2047delTGa
| p.V684Dfs*14 | 13 | Causal | Argentina | 1 | InSIGHT | |
c.2131C > T | p.R711X | 13 | Causal | Brazil | 1 | InSIGHT | |
c.2152C > T | p.Q718X | 13 | Causal | Brazil | 6 | InSIGHT | |
c.2185_2192del7insCCCTa
| p.M729_E731delinsP729_X730 | 13 | Causal | Chile | 1 | Alvarez et al. 2010 [6] | |
c.2187G > Ta
| p.M729I | 13 | VUS | Brazil | 1 | Valentin et al. 2011 [3] | |
c.2525_2526delAGa
| p.E842VfsX3 | 15 | Causal | Brazil | 2 | Valentin et al. 2011 [3] | |
c.2785C > Ta
| p.R929X | 16 | Causal | Brazil | 1 | Valentin et al. 2011 [3] |
Country | Gene | Nucleotide | Consequence | Exon | Polyphen | SIFT | MAP_MMR | P-mut | PON-MMR | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Score | Classification | Score | Classification | Score | Classification | Score | Classification | Score | Classification | |||||
Uruguay |
MLH1
| c.289 T > G | p.Y97D | 3 | 0.999 | Probably damaging | 0 | Damaging | 10.51 | Damaging | 0.7266 | Pathological | 0.83 | Pathogenic |
Argentina |
MLH1
| c.336 T > A | p.H112Q | 4 | 1 | Probably damaging | 0.03 | Damaging | 2.430 | Neutral | NA | NA | 0.61 | VUS |
Colombia |
MLH1
| c.421C > G | p.P141A | 5 | 0.329 | Benign | 0.05 | Damaging | 3.15 | Borderline deleterious | 0.4928 | Neutral | 0.48 | VUS |
Chile |
MLH1
| c.794G > C | p.R265P | 10 | 1 | Probably damaging | 0 | Damaging | 38.09 | Damaging | 0.7623 | Pathological | 0.83 | Pathogenic |
Brazil |
MLH1
| c.1013A > G | p.N338S | 11 | 0.506 | Possibly Damaging | 0.05 | Damaging | 2.78 | Neutral | 0.2551 | Neutral | 0.38 | VUS |
Colombia |
MLH1
| c.1558 + 14G > A | 13 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
Argentina |
MLH1
| c.1724G > A | p.R575K | 15 | 0.001 | Benign | 0.40 | Tolerated | 1.490 | Neutral | NA | NA | 0.15 | Neutral |
Brazil |
MLH1
| c.1853A > C | p.K618T | 16 | 0.997 | Probably damaging | 0.02 | Damaging | 5.11 | Damaging | 0.7802 | Pathological | 0.67 | VUS |
Colombia |
MLH1
| c.1918C > T | p.P640T | 17 | 1 | Probably damaging | 0 | Damaging | 17.77 | Damaging | 0.6534 | Pathological | 0.83 | Pathogenic |
Brazil |
MLH1
| c.2252_2253dupAA | p.V752Kfs*26 | 19 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
Brazil |
MSH2
| c.2187G > T | p.M729I | 13 | 2.293 | Probably damaging | 0 | Damaging | 21.99 | Damaging | 0.1988 | Neutral | 0.71 | VUS |