Introduction
Methods
Samples for mutation analysis
Germline mutation analysis
Results
Coverage
Truncating mutations
Exon | Nucleotide changea
| Predicted protein changea
| dbSNP ID | First reported | HAPS cases (n = 997)b
| FCC-ViP cases (n = 999)b
| Controls (n = 1998)b
| CADD scaled C score |
---|---|---|---|---|---|---|---|---|
3 | c.172_175delTTGT | p.Gln60Argfs*7 | . | Jones (2009) | - | 1 | - | 19.0 |
3 | c.196C > T | p.Gln66* | rs180177083 | Casadei (2011) [29] | 2 | - | - | 35.0 |
4 | c.522_523delAA | p.Arg175Thrfs*9 | . | - | - | 1 | - | 23.2 |
4 | c.577dupA | p.Thr193Asnfs*2 | . | - | 1 | - | - | 11.6 |
4 | c.693dupA | p.Gly232Argfs*3 | . | - | 1 | - | - | 11.2 |
4 | c.758dupT | p.Ser254Ilefs*3 | . | Zheng (2012) [40] | 1 | 1 | - | 16.2 |
4 | c.860dupT | p.Ser288Lysfs*15 | . | - | 1 | - | - | 17.6 |
5 | c.1947dupA | p.Glu650Argfs*13 | . | Teo (2013) [8] | - | 1 | - | 24.1 |
5 | c.1947_1966dup | p.Pro656Glnfs*11 | . | - | 1 | - | - | 13.0 |
5 | c.2386G > T | p.Gly796* | rs180177112 | Rahman (2007) [3] | - | 1 | - | 32.0 |
5 | c.2391delA | p.Gln797Hisfs*54 | . | Wong-Brown (2013) | 1 | - | - | 23.5 |
9 | c.2966_2967insCAACAAGT | p.Glu990Asnfs*3 | . | - | - | - | 1 | 20.7 |
9 | c.2982dupT | p.Ala995Cysfs*16 | rs180177127 | Rahman (2007) [3] | 1 | - | - | 31.0 |
10 | c.3113G > A | p.Trp1038*c
| rs180177132 | Rahman (2007) [3] | 2 | 5 | 1 | 42.0 |
11 | c.3116delA | p.Asn1039Ilefs*2 | rs180177133 | - | 1 | 1 | 40.0 | |
12 | c.3256C > T | p.Arg1086* | . | Jones (2009) | - | 1 | - | 40.0 |
13 | c.3362delG | p.Gly1121Valfs*3 | . | Blanco (2013) [27] | - | 1 | 1 | 22.1 |
13 | c.3507_3508del | p.His1170Phefs*19 | . | Antoniou (2014) [5] | 1 | - | - | 40.0 |
13 | c.3549C > G | p.Tyr1183* | rs118203998 | Reid (2007) [2] | 1 | - | - | 37.0 |
Case | Varianta
| Diagnosis | Family history first-degree relatives | Family history other relatives |
---|---|---|---|---|
HAPS-102285 | p.Gln66* | Breast 41 | NA | NA |
HAPS-60382 | p.Gln66* | Breast 43 | Mother breast 61; father prostate 65 | Paternal: 2 x 2nd cousins breast 42, 37; 3 x great aunt breast 42, 47,58; grandfather prostate 71. Maternal: grandmother other 60 |
HAPS-90978 |
p.Thr193Asnfs*2
| Bilateral breast 61 | Sister breast 60s; sister breast 60s | |
HAPS-90809 |
p.Gly232Argfs*3
| Bilateral breast 41, 47 | Father lung 68 | Cousin breast 45, maternal grandmother bowel 60 |
HAPS-120272 | p.Ser254Ilefs*3 | Breast 35, ovarian 58 | 2 x Sisters breast 40s; brother renal 52; brother HNSCC 50s; father other | Cousin breast 50s. |
HAPS-102573 |
p.Ser288Lysfs*15
| Breast 63 | NA | NA |
HAPS-114269 |
p.Pro656Glnfs*11
| Breast 46, ovarian 49 | Mother unknown primary 45 | Maternal aunt breast 50s; grandmother breast 60s; maternal uncle prostate 70s |
HAPS-120953 | p.Gln797Hisfs*54 | Breast 46 | Father melanoma 62 | half-brother NHL 64; half-brother bladder 55; maternal cousin breast 41; maternal aunt breast 55 |
HAPS-81242 | p.Ala995Cysfs*16 | Bilateral breast 46, 70 | Sister breast 38; daughter breast 47; daughter cervical 24; mother breast 39 | Paternal cousin breast 60s; maternal cousin other |
HAPS-121549 | p.Trp1038* | Breast 56 | Sister breast 44 | Maternal aunt breast 50s; paternal grandmother breast |
HAPS-110283 | p.Trp1038* | Breast 46 | Mother breast 57 | Maternal: aunt bowel 50; great-grandmother ovarian. Paternal: grandmother breast 85, grandfather bowel 60 |
HAPS-100240 | p.His1170Phefs*19 | Breast 48 | Mother breast 68 | Maternal grandmother AML 72; paternal cousin ovarian 36. |
HAPS-110583 | p.Tyr1183* | Breast 39 | Mother breast 80; father bowel 69 | Maternal aunt bilateral breast 50,70; maternal grandfather prostate 80 |
FCC-681-000 | p.Gln60Argfs*7 | Breast 47 | Breast >40 | |
FCC-2121-000 | p.Gly796* | Breast 62 | Lung/prostate | Prostate, other x 2 |
FCC-1423-000 | p.Trp1038* | Breast 44 | Breast >40, bowel, other | Breast >40 |
FCC-2104-000 | p.Trp1038* | Breast 38 | Breast >40, other x 2 | Other |
FCC-2677-000 | p.Trp1038* | Cervix 55, breast 65, 67, 68, bowel 67 | Breast >40, ovarian | Lung, other |
FCC-3527-000 | p.Trp1038* | Breast 37 | Other | |
FCC-60-000 | p.Trp1038* | Thyroid 42, breast 48, 51 | Breast >40, bowel | Breast x 2 ovarian, prostate x 2, lung, other x 2 |
FCC-905-000 | p.Asn1039Ilefs*2 | Melanoma 39, breast 47 | Lung, prostate, other | Breast x 3, bowel x 2, ovarian |
FCC-2965-000 | p.Arg1086* | Bilateral breast 44 | Prostate | |
FCC-317-000 | p.Gly1121Valfs*3 | Breast 31 | Other x 2 | Breast, other |
FCC-1322-000 | p.Glu650Argfs*13 | Breast 50 | Breast, other | Breast x 3, other |
FCC-3397-000 | p.Ser254Ilefs*3 | Melanoma 53, Breast 54, 61 | Breast | |
FCC_2431-000 |
p.Arg175Thrfs*9
| Breast 42 | Breast, other x 3 | Breast x 3, lung, other x 2 |
Controls
|
Variant
|
Age enrolled
|
Family history first-degree relatives
|
Family history other relatives
|
LP-12031915 | p.Trp1038* | 65 | Mother, other 58; father lung 64; brother other | Maternal aunt breast >40 |
LP-13099711 | p.Asn1039Ilefs*2 | 73 | Mother breast 72 | Maternal: grandmother breast >40 yrs; aunt breast |
LP-13243620 |
p.Glu990Asnfs*3
| 73 | Mother breast 82 | NA |
LP-12025195 | p.Gly1121Valfs*3 | 48 | None | Yes, no details |
Missense and synonymous variants
Exon | Nucleotide changea
| Protein changea
| dbSNP ID | First reported | 1000 G MAFb
| NHBLI GO ESP MAFc
| ExACd
| HAPS cases (n = 997)e
| FCC-ViP cases (n = 999)e
| Controls (n = 1998)e
| CADD scaled C score | Condel | PolyPhen2 | SIFT |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | c.11C > T | p.Pro4Leu | rs45619737 | Rahman (2007) [3] | . | 0.00038 | 0.0000999 | 1 | 1 | 1 | 12.9 | Deleterious | Probably damaging | Tolerated |
2 | c.53A > G | p.Lys18Arg | rs138789658 | Tischkowitz (2008) | 0.0032 | 0.00523 | 0.0000552 | - | - | 1 | 18.0 | Deleterious | Possibly damaging | Deleterious |
2 | c.94C > G | p.Leu32Val | rs151316635 | Teo (2013) [8] | . | 0.00023 | 0.0000184 | - | 1 | 1 | 16.3 | Deleterious | Possibly damaging | Deleterious |
3 | c.194C > T | p.Pro65Leu | rs62625272 | Adank (2011) [26] | . | 0.00015 | 0.00006 | - | - | 1 | 4.6 | Neutral | Benign | Tolerated |
4 | c.232G > A | p.Val78Ile | . | Tischkowitz (2012) [39] | . | . | 0.000325 | 2 | 0.4 | Neutral | Benign | Tolerated | ||
4 | c.298C > T | p.Leu100Phe | rs61756147 | Wong (2011) [9] | 0.0005 | 0.00023 | 0.000037 | - | - | 2 | 10.3 | Neutral | Probably damaging | Tolerated |
4 | c.344G > T | p.Gly115Val | rs145598272 | Foulkes (2007) [34] | . | 0.00015 | 0.0000921 | 1 | - | 1 | 6.5 | Neutral | Benign | Tolerated |
4 | c.353 T > C | p.Ile118Thr | . | - | . | 0.00008 | 0.000037 | - | - | 1 | 5.4 | Neutral | Benign | Tolerated |
4 | c.400G > A | p.Asp134Asn | rs139555085 | Zheng (2011) | 0.0005 | 0.00184 | 0 | 1 | 4.8 | Neutral | Benign | Tolerated | ||
4 | c.508A > G | p.Arg170Gly | . | - | . | . | . | - | - | 1 | 4.4 | Neutral | Benign | Tolerated |
4 | c.557A > T | p.Asn186Ile | . | - | . | . | . | - | - | 1 | 13.1 | Deleterious | Probably damaging | Deleterious |
4 | c.571C > G | p.Pro191Ala | . | - | . | . | . | - | - | 1 | 9.4 | Neutral | Probably damaging | Tolerated |
4 | c.629C > T | p.Pro210Leu | rs57605939 | Rahman (2007) [3] | 0.0174 | 0.02216 | 0.0000736 | 1 | 1 | 2 | 10.6 | Deleterious | Probably damaging | Tolerated |
4 | c.899C > T | p.Thr300Ile | . | Ding (2011) | . | . | 0 | 1 | - | - | 15.1 | Deleterious | Probably damaging | Tolerated |
4 | c.656A > G | p.Asp219Gly | rs45594034 | Rahman (2007) [3] | . | 0.00015 | 0.000221 | 1 | 1.8 | Neutral | Benign | Tolerated | ||
4 | c.740C > G | p.Thr247Arg | . | . | . | . | . | 1 | 15.5 | Deleterious | Probably damaging | Tolerated | ||
4 | c.925A > G | p.Ile309Val | rs3809683 | Rahman (2007) [3] | 0.0087 | 0.00970 | 0.0000184 | 4 (1) | - | - | 0.5 | Neutral | Benign | Tolerated |
4 | c.1010 T > C | p.Leu337Ser | rs45494092 | Rahman (2007) [3] | 0.0133 | 0.01424 | 0.0197 | 44 (1) | 44 | 93 (1) | 8.9 | Deleterious | Probably damaging | Tolerated |
4 | c.1085 T > C | p.Leu362Pro | . | - | . | . | . | 1 | - | - | 14.4 | Deleterious | Probably damaging | Tolerated |
4 | c.1145G > T | p.Ser382Ile | . | Tischkowitz (2012) [39] | . | . | 0.0000184 | - | 1 | - | 15.2 | Deleterious | Possibly_damaging | Deleterious |
4 | c.1189A > T | p.Thr397Ser | . | Rahman (2007) [3] | . | 0.00008 | 0.0000184 | - | 1 | 1 | 22.9 | Deleterious | Possibly damaging | Deleterious |
4 | c.1250C > A | p.Ser417Tyr | rs45510998 | Rahman (2007) | . | . | 0.000203 | - | - | 1 | 20.6 | Deleterious | Probably damaging | Deleterious |
4 | c.1478C > T | p.Pro493Leu | . | - | . | . | 0.0000184 | - | - | 1 | 12.4 | Neutral | Benign | Tolerated |
4 | c.1492G > T | p.Asp498Tyr | rs75023630 | Phuah (2013) [38] | 0.0014 | . | 0 | - | - | 1 | 16.2 | Deleterious | Benign | Deleterious |
4 | c.1544A > G | p.Lys515Arg | . | Tischkowitz (2012) [39] | . | . | 0.000037 | - | 1 | - | 16.2 | Deleterious | Possibly damaging | Tolerated |
4 | c.1610C > T | p.Ser537Leu | rs142103232 | - | . | 0.00015 | 0.000166 | - | 1 | - | 11.2 | Neutral | Possibly damaging | Tolerated |
4 | c.1676A > G | p.Gln559Arg | rs152451 | Rahman (2007) [3] | 0.1465 | 0.13483 | 0.0961 | 216 (9) | 182 (11) | 335 (10) | 0.0 | Neutral | Benign | Tolerated |
5 | c.1699C > T | p.His567Tyr | . | Tischkowitz (2012) [39] | . | 0.00008 | 0.000094 | - | - | 1 | 0.9 | Neutral | Benign | Tolerated |
5 | c.1931G > A | p.Gly644Glu | . | - | . | . | . | - | - | 1 | 16.0 | Deleterious | Probably damaging | Deleterious |
5 | c.2014G > C | p.Glu672Gln | rs45532440 | Rahman (2007) [3] | 0.0142 | 0.02324 | 0.0278 | 64 (1) | 68 (4) | 123 (1) | 11.4 | Neutral | Possibly damaging | Tolerated |
5 | c.2106A > G | p.Ile702Met | . | - | . | . | 0.0000184 | 1 | - | - | 11.1 | Neutral | Probably damaging | Tolerated |
5 | c.2135C > T | p.Ala712Val | rs141458731 | Dansonka-Meiszkowska (2010) | 0.0014 | 0.00062 | 0.00039 | - | - | 1 | 12.2 | Neutral | Benign | Tolerated |
5 | c.2200A > T | p.Thr734Ser | rs45543843 | Rahman (2007) [3] | . | . | 0.0000368 | - | - | 3 | 25.3 | Deleterious | Possibly damaging | Deleterious |
5 | c.2228A > G | p.Tyr743Cys | rs141749524 | - | 0.0009 | . | 0.0000184 | 1 | - | - | 8.5 | Neutral | Benign | Tolerated |
5 | c.2289G > C | p.Leu763Phe | . | Phuah (2013) [38] | . | . | 0 | 2 | - | - | 15.5 | Neutral | Probably damaging | Tolerated |
5 | c.2360C > T | p.Thr787Ile | rs201042302 | - | 0.0005 | . | 0 | - | 1 | - | 9.7 | Neutral | Probably damaging | Tolerated |
5 | c.2417C > T | p.Pro806Leu | rs45464991 | Rahman (2007) [3] | . | 0.00008 | 0.000037 | - | 1 | 1 | 0.5 | Neutral | Benign | Tolerated |
7 | c.2590C > T | p.Pro864Ser | rs45568339 | Rahman (2007) [3] | 0.0018 | 0.00239 | 0.00396 | 6 | 10 | 19 | 12.0 | Neutral | Benign | Tolerated |
7 | c.2606C > G | p.Ser869Cys | . | . | . | . | 0.0000184 | 1 | 19.9 | Deleterious | Probably damaging | Deleterious | ||
7 | c.2674G > A | p.Glu892Lys | rs45476495 | Rahman (2007) [3] | . | 0.00008 | 0.000092 | 1 | 2 | - | 20.8 | Deleterious | Possibly damaging | Deleterious |
8 | c.2755G > A | p.Val919Ile | . | - | . | . | . | - | - | 1 | 15.7 | Neutral | Benign | Tolerated |
8 | c.2794G > A | p.Val932Met | rs45624036 | Rahman (2007) [3] | 0.0009 | 0.00431 | 0.00869 | 15 | 8 | 23 | 18.3 | Deleterious | Probably damaging | Tolerated |
8 | c.2816 T > G | p.Leu939Trp | rs45478192 | Rahman (2007) [3] | 0.0009 | 0.00154 | 0.0015 | 2 | 3 (1) | 8 | 20.9 | Deleterious | Probably damaging | Deleterious |
9 | c.2993G > A | p.Gly998Glu | rs45551636 | Rahman (2007) [3] | 0.0105 | 0.01785 | 0.0213 | 42 | 46 (2) | 92 (1) | 22.7 | Deleterious | Probably damaging | Deleterious |
10 | c.3054G > C | p.Glu1018Asp | rs183489969 | Tischkowitz (2012) [39] | 0.0009 | . | 0 | 1 | - | 1 | 16.4 | Deleterious | Possibly damaging | Deleterious |
10 | c.3106G > C | p.Val1036Leu | . | - | . | . | 0.000037 | - | 1 | - | 13.3 | Neutral | Benign | Tolerated |
11 | c.3128G > C | p.Gly1043Ala | . | Hellebrand (2011) [36] | 0.0009 | . | 0.000037 | 1 | - | - | 20.9 | Deleterious | Probably damaging | Deleterious |
11 | c.3146 T > C | p.Met1049Thr | rs138273800 | - | . | 0.00008 | . | - | 1 | - | 18.0 | Deleterious | Probably damaging | Deleterious |
12 | c.3307G > A | p.Val1103Met | rs201657283 | Casadei (2011) [29] | . | 0.00015 | 0.0000184 | - | 1 | - | 13.0 | Neutral | Benign | Tolerated |
13 | c.3366C > A | p.Asp1122Glu | . | . | . | . | . | - | 1 | 16.0 | Neutral | Possibly damaging | Tolerated | |
13 | c.3367G > A | p.Val1123Met | . | . | . | - | 1 | - | 18.7 | Deleterious | Probably damaging | Deleterious | ||
13 | c.3428 T > A | p.Leu1143His | rs62625284 | Balia (2010) | . | 0.00008 | 0.00031 | 2 | - | - | 20.0 | Deleterious | Possibly damaging | Tolerated |
13 | c.3448C > T | p.Leu1150Phe | . | . | . | - | 1 | - | 15.5 | Deleterious | Possibly damaging | Deleterious | ||
13 | c.3449 T > G | p.Leu1150Arg | rs45566737 | . | . | 0.0000368 | - | 1 | - | 18.2 | Deleterious | Possibly damaging | Deleterious |
Exon | Nucleotide changea
| Protein changea
| dbSNP ID | First reported | 1000 G MAFb
| NHBLI GO ESP MAFc
| ExACd
| HAPS cases (n = 997)e
| FCC-ViP cases (n = 999)d
| Controls (n = 1998)e
| CADD scaled C score |
---|---|---|---|---|---|---|---|---|---|---|---|
1 | c.12 T > C | p.(=) | rs145291423 | - | . | . | 0.00012 | - | 1 | 1 | 11.2 |
4 | c.768C > T | p.(=) | rs45487491 | . | . | 0.000037 | 1 | 0.3 | |||
4 | c.1188C > T | p.(=) | . | - | . | . | 0.00003 | - | - | 1 | 7.6 |
4 | c.1194G > A | p.(=) | rs61755173 | Rahman (2007) [3] | 0.0009 | 0.00154 | 0.00114 | 3 | 2 | 8 | 6.4 |
4 | c.1194G > T | p.(=) | . | - | . | . | . | 1 | - | - | 6.1 |
4 | c.1242A > C | p.(=) | . | - | . | . | . | - | - | 1 | 7.7 |
4 | c.1431C > T | p.(=) | . | Teo (2013) | . | . | 0 | 2 | - | - | 0.0 |
4 | c.1470C > T | p.(=) | rs45612837 | Rahman (2007) [3] | 0.0005 | 0.00015 | 0.000405 | 1 | - | 2 | 5.8 |
4 | c.1572A > G | p.(=) | rs45472400 | Rahman (2007) [3] | 0.0032 | 0.00339 | 0.0041 | 12 | 12 | 27 | 5.6 |
4 | c.1623G > A | p.(=) | . | - | . | . | 0 | - | 1 | 2 | 4.2 |
5 | c.2067G > A | p.(=) | . | Phuah (2013) [38] | . | 0.00015 | 0.000018 | 1 | - | - | 4.1 |
5 | c.2082A > G | p.(=) | rs150569240 | - | . | . | 0.000055 | - | - | 1 | 5.8 |
5 | c.2091C > A | p.(=) | . | - | . | . | 0 | - | - | 1 | 4.7 |
5 | c.2244A > G | p.(=) | . | - | . | . | 0.000037 | - | - | 1 | 5.6 |
5 | c.2328C > T | p.(=) | rs45508997 | - | . | 0.00008 | 0 | 1 | - | - | 4.0 |
5 | c.2337A > C | p.(=) | . | - | . | . | . | - | 1 | - | 5.2 |
5 | c.2379C > T | p.(=) | . | - | . | 0.00008 | 0.000111 | 1 | 1 | - | 0.1 |
5 | c.2478C > T | p.(=) | . | - | . | . | . | - | - | 1 | 4.2 |
5 | c.2484C > T | p.(=) | . | - | . | . | . | - | - | 1 | 6.0 |
7 | c.2742C > T | p.(=) | rs115759702 | - | 0.0018 | 0.00146 | 0.00003 | 2 | - | - | 0.7 |
12 | c.3294G > A | p.(=) | . | - | . | . | . | - | - | 1 | 9.9 |
12 | c.3300 T > G | p.(=) | rs45516100 | Rahman (2007) [3] | 0.0183 | 0.02801 | 0.0278 | 64 (1) | 68 (4) | 123 (1) | 7.9 |
13 | c.3495G > A | p.(=) | rs45439097 | Bogdanova (2010) | . | 0.00108 | 0.000994 | 4 | 7 | 9 | 8.6 |