BRCA1 R1699Q variant displaying ambiguous Functional abrogation confers intermediate breast And ovarian cancer risk

Amanda B. Spurdle; Phillip J. Whiley; Bryony Thompson; Bingjian Feng; Sue Healey; Melissa A. Brown; Christopher Pettigrew; Christi J. Van Asperen; Margreet G.E.M. Ausems; Anna A. Kattentidt-Mouravieva; Ans M.W. van den Ouweland; Annika Lindblom; Maritta H. Pigg; Rita K. Schmutzler; Christoph Engel; Alfons Meindl; Sandrine Caputo; Olga M. Sinilnikova; Rosette Lidereau; Fergus J. Couch; Lucia Guidugli; Thomas van Overeem Hansen; Mads Thomassen; Diana M. Eccles; Kathy Tucker; Javier Benitez; Susan M. Domchek; Amanda E. Toland; J Van Rensburg Elizabeth J Van Rensburg; Barbara Wappenschmidt; Åke Borg; Maaike P.G. Vreeswijk; David E. Goldgar; Frans B. Hogervorst; Rogier A. Oldenburg; Juul T. Wijnen; Peter Devilee; Rob B. van der Luijt; Johan J.P. Gille; Muriel A. Adank; Encarna B. Gomez Garcia; Marinus J. Blok; Jan C. Oosterwijk; A. H. van der Hout; Genevieve Michils; Eric Legius; Erik Teugels; de Grève Jacques de Grève; Norbert Arnold; Helmut Deisler; Dorothea Gadzicki; Andrea Gehrig; Wolfram Heinritz; Karin Kast; Dieter Niederacher; Sabine Preisler-Adams; Christian Sutter; Raymonda Varon-Mateeva; Bernhard H. Weber; Nicolas Sévenet; Françoise Bonnet; Michel Longy; Agnès Hardouin; Dominique Vaur; Sophie Krieger; Nancy Uhrhammer; Yves Jean Bignon; Jean Philippe Peyrat; Françoise Revillion; Joëlle Fournier; Sylvie Mazoyer; Mélanie Léone; Hagay Sobol; Tetsuro Noguchi; Violaine Bourdon; Audrey Remenieras; Jean Marc Rey; Myriam Bronner; Joanna Sokolowska-Gillois; Philippe Jonveaux; Capucine Delnatte; Florence Coulet; Laurent Castera; Virginie Caux-Moncoutier; Claude Houdayer; Stoppa-Lyonnet Dominique Stoppa-Lyonnet; Chantal Delvincourt; Marie Claude Gorisse; Ivan Bièche; Cédrick Lefol; Etienne Rouleau; Joseph Abecassis; Danièle Muller; Christine Toulas; Marine Guillaud-Bataille; Brigitte Bressac-de Paillerets; Richard Barber; Tina Bedenham; Lucy Burgess; Joanna Campbell; Jackie Cook; Andrew Devereau; Bent Ejlertsen; Mike Fields; Anne Marie Gerdes; Elizabeth Johnston; Torben A. Kruse; Anita Luharia; Carole Mckeown; Kate Nathanson; Finn C. Nielsen; Leigha Senter; Barbara Stayner; Kevin Sweet; Simon Thomas; Yvonne Wallis; Sally Watts

doi:10.1136/jmedgenet-2012-101037

BRCA1 R1699Q variant displaying ambiguous Functional abrogation confers intermediate breast And ovarian cancer risk

Amanda B. Spurdle, Phillip J. Whiley, Bryony Thompson, Bingjian Feng, Sue Healey, Melissa A. Brown, Christopher Pettigrew, Christi J. Van Asperen, Margreet G.E.M. Ausems, Anna A. Kattentidt-Mouravieva, Ans M.W. van den Ouweland, Annika Lindblom, Maritta H. Pigg, Rita K. Schmutzler, Christoph Engel, Alfons Meindl, Sandrine Caputo, Olga M. Sinilnikova, Rosette Lidereau, Fergus J. CouchLucia Guidugli, Thomas van Overeem Hansen, Mads Thomassen, Diana M. Eccles, Kathy Tucker, Javier Benitez, Susan M. Domchek, Amanda E. Toland, J Van Rensburg Elizabeth J Van Rensburg, Barbara Wappenschmidt, Åke Borg, Maaike P.G. Vreeswijk, David E. Goldgar, Frans B. Hogervorst, Rogier A. Oldenburg, Juul T. Wijnen, Peter Devilee, Rob B. van der Luijt, Johan J.P. Gille, Muriel A. Adank, Encarna B. Gomez Garcia, Marinus J. Blok, Jan C. Oosterwijk, A. H. van der Hout, Genevieve Michils, Eric Legius, Erik Teugels, de Grève Jacques de Grève, Norbert Arnold, Helmut Deisler, Dorothea Gadzicki, Andrea Gehrig, Wolfram Heinritz, Karin Kast, Dieter Niederacher, Sabine Preisler-Adams, Christian Sutter, Raymonda Varon-Mateeva, Bernhard H. Weber, Nicolas Sévenet, Françoise Bonnet, Michel Longy, Agnès Hardouin, Dominique Vaur, Sophie Krieger, Nancy Uhrhammer, Yves Jean Bignon, Jean Philippe Peyrat, Françoise Revillion, Joëlle Fournier, Sylvie Mazoyer, Mélanie Léone, Hagay Sobol, Tetsuro Noguchi, Violaine Bourdon, Audrey Remenieras, Jean Marc Rey, Myriam Bronner, Joanna Sokolowska-Gillois, Philippe Jonveaux, Capucine Delnatte, Florence Coulet, Laurent Castera, Virginie Caux-Moncoutier, Claude Houdayer, Stoppa-Lyonnet Dominique Stoppa-Lyonnet, Chantal Delvincourt, Marie Claude Gorisse, Ivan Bièche, Cédrick Lefol, Etienne Rouleau, Joseph Abecassis, Danièle Muller, Christine Toulas, Marine Guillaud-Bataille, Brigitte Bressac-de Paillerets, Richard Barber, Tina Bedenham, Lucy Burgess, Joanna Campbell, Jackie Cook, Andrew Devereau, Bent Ejlertsen, Mike Fields, Anne Marie Gerdes, Elizabeth Johnston, Torben A. Kruse, Anita Luharia, Carole Mckeown, Kate Nathanson, Finn C. Nielsen, Leigha Senter, Barbara Stayner, Kevin Sweet, Simon Thomas, Yvonne Wallis, Sally Watts

Research output: Contribution to journal › Article › peer-review

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Abstract

Background Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G>A p. Arg1699Gln in the BRCA1 transcriptional transactivation domain demonstrated equivocal results from a series of functional assays, and proposed that this variant may confer low to moderate risk of cancer. Methods Measures of genetic risk (report of family history, segregation) were assessed for 68 BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) families recruited through family cancer clinics, comparing results with 34 families carrying the previously classified pathogenic BRCA1 c.5095C>T p.Arg1699Trp (R1699W) mutation at the same residue, and to 243 breast cancer families with no BRCA1 pathogenic mutation (BRCA-X). Results Comparison of BRCA1 carrier prediction scores of probands using the BOADICEA risk prediction tool revealed that BRCA1 c.5096G>A p.Arg1699Gln variant carriers had family histories that were less 'BRCA1-like' than BRCA1 c.5095C>T p.Arg1699Trp mutation carriers (p<0.00001), but more 'BRCA1-like' than BRCA-X families (p=0.0004). Further, modified segregation analysis of the subset of 30 families with additional genotyping showed that BRCA1 c.5096G >A p. Arg1699Gln had reduced penetrance compared with the average truncating BRCA1 mutation penetrance (p=0.0002), with estimated cumulative risks to age 70 of breast or ovarian cancer of 24%. Conclusions Our results provide substantial evidence that the BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) variant, demonstrating ambiguous functional deficiency across multiple assays, is associated with intermediate risk of breast and ovarian cancer, highlighting challenges for risk modelling and clinical management of patients of this and other potential moderate-risk variants.

Original language	English (US)
Pages (from-to)	525-532
Number of pages	8
Journal	Journal of medical genetics
Volume	49
Issue number	8
DOIs	https://doi.org/10.1136/jmedgenet-2012-101037
State	Published - Aug 2012

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1136/jmedgenet-2012-101037

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Spurdle, A. B., Whiley, P. J., Thompson, B., Feng, B., Healey, S., Brown, M. A., Pettigrew, C., Van Asperen, C. J., Ausems, M. G. E. M., Kattentidt-Mouravieva, A. A., van den Ouweland, A. M. W., Lindblom, A., Pigg, M. H., Schmutzler, R. K., Engel, C., Meindl, A., Caputo, S., Sinilnikova, O. M., Lidereau, R., ... Watts, S. (2012). BRCA1 R1699Q variant displaying ambiguous Functional abrogation confers intermediate breast And ovarian cancer risk. Journal of medical genetics, 49(8), 525-532. https://doi.org/10.1136/jmedgenet-2012-101037

Spurdle, AB, Whiley, PJ, Thompson, B, Feng, B, Healey, S, Brown, MA, Pettigrew, C, Van Asperen, CJ, Ausems, MGEM, Kattentidt-Mouravieva, AA, van den Ouweland, AMW, Lindblom, A, Pigg, MH, Schmutzler, RK, Engel, C, Meindl, A, Caputo, S, Sinilnikova, OM, Lidereau, R, Couch, FJ, Guidugli, L, van Overeem Hansen, T, Thomassen, M, Eccles, DM, Tucker, K, Benitez, J, Domchek, SM, Toland, AE, Elizabeth J Van Rensburg, JVR, Wappenschmidt, B, Borg, Å, Vreeswijk, MPG, Goldgar, DE, Hogervorst, FB, Oldenburg, RA, Wijnen, JT, Devilee, P, van der Luijt, RB, Gille, JJP, Adank, MA, Gomez Garcia, EB, Blok, MJ, Oosterwijk, JC, van der Hout, AH, Michils, G, Legius, E, Teugels, E, Jacques de Grève, DG, Arnold, N, Deisler, H, Gadzicki, D, Gehrig, A, Heinritz, W, Kast, K, Niederacher, D, Preisler-Adams, S, Sutter, C, Varon-Mateeva, R, Weber, BH, Sévenet, N, Bonnet, F, Longy, M, Hardouin, A, Vaur, D, Krieger, S, Uhrhammer, N, Bignon, YJ, Peyrat, JP, Revillion, F, Fournier, J, Mazoyer, S, Léone, M, Sobol, H, Noguchi, T, Bourdon, V, Remenieras, A, Rey, JM, Bronner, M, Sokolowska-Gillois, J, Jonveaux, P, Delnatte, C, Coulet, F, Castera, L, Caux-Moncoutier, V, Houdayer, C, Dominique Stoppa-Lyonnet, S-L, Delvincourt, C, Gorisse, MC, Bièche, I, Lefol, C, Rouleau, E, Abecassis, J, Muller, D, Toulas, C, Guillaud-Bataille, M, Bressac-de Paillerets, B, Barber, R, Bedenham, T, Burgess, L, Campbell, J, Cook, J, Devereau, A, Ejlertsen, B, Fields, M, Gerdes, AM, Johnston, E, Kruse, TA, Luharia, A, Mckeown, C, Nathanson, K, Nielsen, FC, Senter, L, Stayner, B, Sweet, K, Thomas, S, Wallis, Y & Watts, S 2012, 'BRCA1 R1699Q variant displaying ambiguous Functional abrogation confers intermediate breast And ovarian cancer risk', Journal of medical genetics, vol. 49, no. 8, pp. 525-532. https://doi.org/10.1136/jmedgenet-2012-101037

@article{18bbb37e122e4e28974c3c240a72b05b,

title = "BRCA1 R1699Q variant displaying ambiguous Functional abrogation confers intermediate breast And ovarian cancer risk",

abstract = "Background Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G>A p. Arg1699Gln in the BRCA1 transcriptional transactivation domain demonstrated equivocal results from a series of functional assays, and proposed that this variant may confer low to moderate risk of cancer. Methods Measures of genetic risk (report of family history, segregation) were assessed for 68 BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) families recruited through family cancer clinics, comparing results with 34 families carrying the previously classified pathogenic BRCA1 c.5095C>T p.Arg1699Trp (R1699W) mutation at the same residue, and to 243 breast cancer families with no BRCA1 pathogenic mutation (BRCA-X). Results Comparison of BRCA1 carrier prediction scores of probands using the BOADICEA risk prediction tool revealed that BRCA1 c.5096G>A p.Arg1699Gln variant carriers had family histories that were less 'BRCA1-like' than BRCA1 c.5095C>T p.Arg1699Trp mutation carriers (p<0.00001), but more 'BRCA1-like' than BRCA-X families (p=0.0004). Further, modified segregation analysis of the subset of 30 families with additional genotyping showed that BRCA1 c.5096G >A p. Arg1699Gln had reduced penetrance compared with the average truncating BRCA1 mutation penetrance (p=0.0002), with estimated cumulative risks to age 70 of breast or ovarian cancer of 24%. Conclusions Our results provide substantial evidence that the BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) variant, demonstrating ambiguous functional deficiency across multiple assays, is associated with intermediate risk of breast and ovarian cancer, highlighting challenges for risk modelling and clinical management of patients of this and other potential moderate-risk variants.",

author = "Spurdle, {Amanda B.} and Whiley, {Phillip J.} and Bryony Thompson and Bingjian Feng and Sue Healey and Brown, {Melissa A.} and Christopher Pettigrew and {Van Asperen}, {Christi J.} and Ausems, {Margreet G.E.M.} and Kattentidt-Mouravieva, {Anna A.} and {van den Ouweland}, {Ans M.W.} and Annika Lindblom and Pigg, {Maritta H.} and Schmutzler, {Rita K.} and Christoph Engel and Alfons Meindl and Sandrine Caputo and Sinilnikova, {Olga M.} and Rosette Lidereau and Couch, {Fergus J.} and Lucia Guidugli and {van Overeem Hansen}, Thomas and Mads Thomassen and Eccles, {Diana M.} and Kathy Tucker and Javier Benitez and Domchek, {Susan M.} and Toland, {Amanda E.} and {Elizabeth J Van Rensburg}, {J Van Rensburg} and Barbara Wappenschmidt and {\AA}ke Borg and Vreeswijk, {Maaike P.G.} and Goldgar, {David E.} and Hogervorst, {Frans B.} and Oldenburg, {Rogier A.} and Wijnen, {Juul T.} and Peter Devilee and {van der Luijt}, {Rob B.} and Gille, {Johan J.P.} and Adank, {Muriel A.} and {Gomez Garcia}, {Encarna B.} and Blok, {Marinus J.} and Oosterwijk, {Jan C.} and {van der Hout}, {A. H.} and Genevieve Michils and Eric Legius and Erik Teugels and {Jacques de Gr{\`e}ve}, {de Gr{\`e}ve} and Norbert Arnold and Helmut Deisler and Dorothea Gadzicki and Andrea Gehrig and Wolfram Heinritz and Karin Kast and Dieter Niederacher and Sabine Preisler-Adams and Christian Sutter and Raymonda Varon-Mateeva and Weber, {Bernhard H.} and Nicolas S{\'e}venet and Fran{\c c}oise Bonnet and Michel Longy and Agn{\`e}s Hardouin and Dominique Vaur and Sophie Krieger and Nancy Uhrhammer and Bignon, {Yves Jean} and Peyrat, {Jean Philippe} and Fran{\c c}oise Revillion and Jo{\"e}lle Fournier and Sylvie Mazoyer and M{\'e}lanie L{\'e}one and Hagay Sobol and Tetsuro Noguchi and Violaine Bourdon and Audrey Remenieras and Rey, {Jean Marc} and Myriam Bronner and Joanna Sokolowska-Gillois and Philippe Jonveaux and Capucine Delnatte and Florence Coulet and Laurent Castera and Virginie Caux-Moncoutier and Claude Houdayer and {Dominique Stoppa-Lyonnet}, Stoppa-Lyonnet and Chantal Delvincourt and Gorisse, {Marie Claude} and Ivan Bi{\`e}che and C{\'e}drick Lefol and Etienne Rouleau and Joseph Abecassis and Dani{\`e}le Muller and Christine Toulas and Marine Guillaud-Bataille and {Bressac-de Paillerets}, Brigitte and Richard Barber and Tina Bedenham and Lucy Burgess and Joanna Campbell and Jackie Cook and Andrew Devereau and Bent Ejlertsen and Mike Fields and Gerdes, {Anne Marie} and Elizabeth Johnston and Kruse, {Torben A.} and Anita Luharia and Carole Mckeown and Kate Nathanson and Nielsen, {Finn C.} and Leigha Senter and Barbara Stayner and Kevin Sweet and Simon Thomas and Yvonne Wallis and Sally Watts",

year = "2012",

month = aug,

doi = "10.1136/jmedgenet-2012-101037",

language = "English (US)",

volume = "49",

pages = "525--532",

journal = "Journal of medical genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "8",

}

TY - JOUR

T1 - BRCA1 R1699Q variant displaying ambiguous Functional abrogation confers intermediate breast And ovarian cancer risk

AU - Spurdle, Amanda B.

AU - Whiley, Phillip J.

AU - Thompson, Bryony

AU - Feng, Bingjian

AU - Healey, Sue

AU - Brown, Melissa A.

AU - Pettigrew, Christopher

AU - Van Asperen, Christi J.

AU - Ausems, Margreet G.E.M.

AU - Kattentidt-Mouravieva, Anna A.

AU - van den Ouweland, Ans M.W.

AU - Lindblom, Annika

AU - Pigg, Maritta H.

AU - Schmutzler, Rita K.

AU - Engel, Christoph

AU - Meindl, Alfons

AU - Caputo, Sandrine

AU - Sinilnikova, Olga M.

AU - Lidereau, Rosette

AU - Couch, Fergus J.

AU - Guidugli, Lucia

AU - van Overeem Hansen, Thomas

AU - Thomassen, Mads

AU - Eccles, Diana M.

AU - Tucker, Kathy

AU - Benitez, Javier

AU - Domchek, Susan M.

AU - Toland, Amanda E.

AU - Elizabeth J Van Rensburg, J Van Rensburg

AU - Wappenschmidt, Barbara

AU - Borg, Åke

AU - Vreeswijk, Maaike P.G.

AU - Goldgar, David E.

AU - Hogervorst, Frans B.

AU - Oldenburg, Rogier A.

AU - Wijnen, Juul T.

AU - Devilee, Peter

AU - van der Luijt, Rob B.

AU - Gille, Johan J.P.

AU - Adank, Muriel A.

AU - Gomez Garcia, Encarna B.

AU - Blok, Marinus J.

AU - Oosterwijk, Jan C.

AU - van der Hout, A. H.

AU - Michils, Genevieve

AU - Legius, Eric

AU - Teugels, Erik

AU - Jacques de Grève, de Grève

AU - Arnold, Norbert

AU - Deisler, Helmut

AU - Gadzicki, Dorothea

AU - Gehrig, Andrea

AU - Heinritz, Wolfram

AU - Kast, Karin

AU - Niederacher, Dieter

AU - Preisler-Adams, Sabine

AU - Sutter, Christian

AU - Varon-Mateeva, Raymonda

AU - Weber, Bernhard H.

AU - Sévenet, Nicolas

AU - Bonnet, Françoise

AU - Longy, Michel

AU - Hardouin, Agnès

AU - Vaur, Dominique

AU - Krieger, Sophie

AU - Uhrhammer, Nancy

AU - Bignon, Yves Jean

AU - Peyrat, Jean Philippe

AU - Revillion, Françoise

AU - Fournier, Joëlle

AU - Mazoyer, Sylvie

AU - Léone, Mélanie

AU - Sobol, Hagay

AU - Noguchi, Tetsuro

AU - Bourdon, Violaine

AU - Remenieras, Audrey

AU - Rey, Jean Marc

AU - Bronner, Myriam

AU - Sokolowska-Gillois, Joanna

AU - Jonveaux, Philippe

AU - Delnatte, Capucine

AU - Coulet, Florence

AU - Castera, Laurent

AU - Caux-Moncoutier, Virginie

AU - Houdayer, Claude

AU - Dominique Stoppa-Lyonnet, Stoppa-Lyonnet

AU - Delvincourt, Chantal

AU - Gorisse, Marie Claude

AU - Bièche, Ivan

AU - Lefol, Cédrick

AU - Rouleau, Etienne

AU - Abecassis, Joseph

AU - Muller, Danièle

AU - Toulas, Christine

AU - Guillaud-Bataille, Marine

AU - Bressac-de Paillerets, Brigitte

AU - Barber, Richard

AU - Bedenham, Tina

AU - Burgess, Lucy

AU - Campbell, Joanna

AU - Cook, Jackie

AU - Devereau, Andrew

AU - Ejlertsen, Bent

AU - Fields, Mike

AU - Gerdes, Anne Marie

AU - Johnston, Elizabeth

AU - Kruse, Torben A.

AU - Luharia, Anita

AU - Mckeown, Carole

AU - Nathanson, Kate

AU - Nielsen, Finn C.

AU - Senter, Leigha

AU - Stayner, Barbara

AU - Sweet, Kevin

AU - Thomas, Simon

AU - Wallis, Yvonne

AU - Watts, Sally

PY - 2012/8

Y1 - 2012/8

N2 - Background Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G>A p. Arg1699Gln in the BRCA1 transcriptional transactivation domain demonstrated equivocal results from a series of functional assays, and proposed that this variant may confer low to moderate risk of cancer. Methods Measures of genetic risk (report of family history, segregation) were assessed for 68 BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) families recruited through family cancer clinics, comparing results with 34 families carrying the previously classified pathogenic BRCA1 c.5095C>T p.Arg1699Trp (R1699W) mutation at the same residue, and to 243 breast cancer families with no BRCA1 pathogenic mutation (BRCA-X). Results Comparison of BRCA1 carrier prediction scores of probands using the BOADICEA risk prediction tool revealed that BRCA1 c.5096G>A p.Arg1699Gln variant carriers had family histories that were less 'BRCA1-like' than BRCA1 c.5095C>T p.Arg1699Trp mutation carriers (p<0.00001), but more 'BRCA1-like' than BRCA-X families (p=0.0004). Further, modified segregation analysis of the subset of 30 families with additional genotyping showed that BRCA1 c.5096G >A p. Arg1699Gln had reduced penetrance compared with the average truncating BRCA1 mutation penetrance (p=0.0002), with estimated cumulative risks to age 70 of breast or ovarian cancer of 24%. Conclusions Our results provide substantial evidence that the BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) variant, demonstrating ambiguous functional deficiency across multiple assays, is associated with intermediate risk of breast and ovarian cancer, highlighting challenges for risk modelling and clinical management of patients of this and other potential moderate-risk variants.

AB - Background Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G>A p. Arg1699Gln in the BRCA1 transcriptional transactivation domain demonstrated equivocal results from a series of functional assays, and proposed that this variant may confer low to moderate risk of cancer. Methods Measures of genetic risk (report of family history, segregation) were assessed for 68 BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) families recruited through family cancer clinics, comparing results with 34 families carrying the previously classified pathogenic BRCA1 c.5095C>T p.Arg1699Trp (R1699W) mutation at the same residue, and to 243 breast cancer families with no BRCA1 pathogenic mutation (BRCA-X). Results Comparison of BRCA1 carrier prediction scores of probands using the BOADICEA risk prediction tool revealed that BRCA1 c.5096G>A p.Arg1699Gln variant carriers had family histories that were less 'BRCA1-like' than BRCA1 c.5095C>T p.Arg1699Trp mutation carriers (p<0.00001), but more 'BRCA1-like' than BRCA-X families (p=0.0004). Further, modified segregation analysis of the subset of 30 families with additional genotyping showed that BRCA1 c.5096G >A p. Arg1699Gln had reduced penetrance compared with the average truncating BRCA1 mutation penetrance (p=0.0002), with estimated cumulative risks to age 70 of breast or ovarian cancer of 24%. Conclusions Our results provide substantial evidence that the BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) variant, demonstrating ambiguous functional deficiency across multiple assays, is associated with intermediate risk of breast and ovarian cancer, highlighting challenges for risk modelling and clinical management of patients of this and other potential moderate-risk variants.

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U2 - 10.1136/jmedgenet-2012-101037

DO - 10.1136/jmedgenet-2012-101037

M3 - Article

C2 - 22889855

AN - SCOPUS:84866329098

SN - 0022-2593

VL - 49

SP - 525

EP - 532

JO - Journal of medical genetics

JF - Journal of medical genetics

IS - 8

ER -

BRCA1 R1699Q variant displaying ambiguous Functional abrogation confers intermediate breast And ovarian cancer risk

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