Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms

Miguel de la Hoya; Omar Soukarieh; Irene López-perolio; Ana Vega; Logan C Walker; Yvette Van Ierland; Diana Baralle; Marta Santamariña; Vanessa Lattimore; Juul Wijnen; Philip Whiley; Ana Blanco; Michela Raponi; Jan Hauke; Barbara Wappenschmidt; Alexandra Becker; Thomas v O Hansen; Raquel Behar; Kconfab Investigators; Diether Niederacher; Norbert Arnold; Bernd Dworniczak; Doris Steinemann; Ulrike Faust; Wendy Rubinstein; Peter J Hulick; Claude Houdayer; Sandrine M. Caputo; Laurent Castera; Tina Pesaran; Elizabeth Chao; Carole Brewer; Melissa C Southey; Christi J van Asperen; Christian F Singer; Jan Sullivan; Nicola Poplawski; Phuong L Mai; Julian Peto; Nichola Johnson; Barbara Burwinkel; Harald M Surowy; Stig E. Bojesen; Henrik Flyger; Annika Lindblom; Sara Margolin; Jenny Chang-Claude; Anja Rudolph; Paolo Radice; Laura Galastri; Janet E Olson; Emily Hallberg; Graham Giles; Roger L Milne; Irene L Andrulis; Gord Glendon; Per Hall; Kamila Czene; Fiona Blows; Mitul Shah; Qin Wang; Joe Dennis; Kyriaki Michailidou; Lesley McGuffog; Manjeet K Bolla; Antonis C Antoniou; Douglas F Easton; Fergus J Couch; Sean Tavtigian; Maaike P Vreeswijk; Michael Parsons; Huong D Meeks; Alexandra Martins; David E Goldgar; Amanda B Spurdle

doi:10.1093/hmg/ddw094

Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms

Miguel de la Hoya, Omar Soukarieh, Irene López-perolio, Ana Vega, Logan C Walker, Yvette Van Ierland, Diana Baralle, Marta Santamariña, Vanessa Lattimore, Juul Wijnen, Philip Whiley, Ana Blanco, Michela Raponi, Jan Hauke, Barbara Wappenschmidt, Alexandra Becker, Thomas v O Hansen, Raquel Behar, Kconfab Investigators, Diether NiederacherNorbert Arnold, Bernd Dworniczak, Doris Steinemann, Ulrike Faust, Wendy Rubinstein, Peter J Hulick, Claude Houdayer, Sandrine M. Caputo, Laurent Castera, Tina Pesaran, Elizabeth Chao, Carole Brewer, Melissa C Southey, Christi J van Asperen, Christian F Singer, Jan Sullivan, Nicola Poplawski, Phuong L Mai, Julian Peto, Nichola Johnson, Barbara Burwinkel, Harald M Surowy, Stig E. Bojesen, Henrik Flyger, Annika Lindblom, Sara Margolin, Jenny Chang-Claude, Anja Rudolph, Paolo Radice, Laura Galastri, Janet E Olson, Emily Hallberg, Graham Giles, Roger L Milne, Irene L Andrulis, Gord Glendon, Per Hall, Kamila Czene, Fiona Blows, Mitul Shah, Qin Wang, Joe Dennis, Kyriaki Michailidou, Lesley McGuffog, Manjeet K Bolla, Antonis C Antoniou, Douglas F Easton, Fergus J Couch, Sean Tavtigian, Maaike P Vreeswijk, Michael Parsons, Huong D Meeks, Alexandra Martins, David E Goldgar, Amanda B Spurdle

Department of Clinical Medicine

44 Citations (Scopus)

Abstract

A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A>C (IVS9-2A>C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A>C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 x 10^-8. Our data indicate that c.594-2A>C is always in cis with c.641A>G. The spliceogenic effect of c.[594-2A>C;641A>G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A>C; 641A>G] caused exon 10 skipping, albeit not due to c.594-2A>C impairing the acceptor site but rather by c.641A>G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of70-80% truncating transcripts, and20-30% of in-frame D9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function. We confirm that BRCA1c.[594-2A>C;641A>G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes.

Original language	English
Journal	Human Molecular Genetics
Volume	25
Issue number	11
Pages (from-to)	2256-2268
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/ddw094
Publication status	Published - 1 Jun 2016

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de la Hoya, M., Soukarieh, O., López-perolio, I., Vega, A., Walker, L. C., Van Ierland, Y., Baralle, D., Santamariña, M., Lattimore, V., Wijnen, J., Whiley, P., Blanco, A., Raponi, M., Hauke, J., Wappenschmidt, B., Becker, A., Hansen, T. V. O., Behar, R., Investigators, K., ... Spurdle, A. B. (2016). Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms. Human Molecular Genetics, 25(11), 2256-2268. https://doi.org/10.1093/hmg/ddw094

Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms. / de la Hoya, Miguel; Soukarieh, Omar; López-perolio, Irene et al.
In: Human Molecular Genetics, Vol. 25, No. 11, 01.06.2016, p. 2256-2268.

Research output: Contribution to journal › Journal article › Research › peer-review

de la Hoya, M, Soukarieh, O, López-perolio, I, Vega, A, Walker, LC, Van Ierland, Y, Baralle, D, Santamariña, M, Lattimore, V, Wijnen, J, Whiley, P, Blanco, A, Raponi, M, Hauke, J, Wappenschmidt, B, Becker, A, Hansen, TVO, Behar, R, Investigators, K, Niederacher, D, Arnold, N, Dworniczak, B, Steinemann, D, Faust, U, Rubinstein, W, Hulick, PJ, Houdayer, C, Caputo, SM, Castera, L, Pesaran, T, Chao, E, Brewer, C, Southey, MC, van Asperen, CJ, Singer, CF, Sullivan, J, Poplawski, N, Mai, PL, Peto, J, Johnson, N, Burwinkel, B, Surowy, HM, Bojesen, SE, Flyger, H, Lindblom, A, Margolin, S, Chang-Claude, J, Rudolph, A, Radice, P, Galastri, L, Olson, JE, Hallberg, E, Giles, G, Milne, RL, Andrulis, IL, Glendon, G, Hall, P, Czene, K, Blows, F, Shah, M, Wang, Q, Dennis, J, Michailidou, K, McGuffog, L, Bolla, MK, Antoniou, AC, Easton, DF, Couch, FJ, Tavtigian, S, Vreeswijk, MP, Parsons, M, Meeks, HD, Martins, A, Goldgar, DE & Spurdle, AB 2016, 'Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms', Human Molecular Genetics, vol. 25, no. 11, pp. 2256-2268. https://doi.org/10.1093/hmg/ddw094

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title = "Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms",

abstract = "A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A>C (IVS9-2A>C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A>C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 x 10-8. Our data indicate that c.594-2A>C is always in cis with c.641A>G. The spliceogenic effect of c.[594-2A>C;641A>G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A>C; 641A>G] caused exon 10 skipping, albeit not due to c.594-2A>C impairing the acceptor site but rather by c.641A>G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of70-80% truncating transcripts, and20-30% of in-frame D9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function. We confirm that BRCA1c.[594-2A>C;641A>G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes.",

author = "{de la Hoya}, Miguel and Omar Soukarieh and Irene L{\'o}pez-perolio and Ana Vega and Walker, {Logan C} and {Van Ierland}, Yvette and Diana Baralle and Marta Santamari{\~n}a and Vanessa Lattimore and Juul Wijnen and Philip Whiley and Ana Blanco and Michela Raponi and Jan Hauke and Barbara Wappenschmidt and Alexandra Becker and Hansen, {Thomas v O} and Raquel Behar and Kconfab Investigators and Diether Niederacher and Norbert Arnold and Bernd Dworniczak and Doris Steinemann and Ulrike Faust and Wendy Rubinstein and Hulick, {Peter J} and Claude Houdayer and Caputo, {Sandrine M.} and Laurent Castera and Tina Pesaran and Elizabeth Chao and Carole Brewer and Southey, {Melissa C} and {van Asperen}, {Christi J} and Singer, {Christian F} and Jan Sullivan and Nicola Poplawski and Mai, {Phuong L} and Julian Peto and Nichola Johnson and Barbara Burwinkel and Surowy, {Harald M} and Bojesen, {Stig E.} and Henrik Flyger and Annika Lindblom and Sara Margolin and Jenny Chang-Claude and Anja Rudolph and Paolo Radice and Laura Galastri and Olson, {Janet E} and Emily Hallberg and Graham Giles and Milne, {Roger L} and Andrulis, {Irene L} and Gord Glendon and Per Hall and Kamila Czene and Fiona Blows and Mitul Shah and Qin Wang and Joe Dennis and Kyriaki Michailidou and Lesley McGuffog and Bolla, {Manjeet K} and Antoniou, {Antonis C} and Easton, {Douglas F} and Couch, {Fergus J} and Sean Tavtigian and Vreeswijk, {Maaike P} and Michael Parsons and Meeks, {Huong D} and Alexandra Martins and Goldgar, {David E} and Spurdle, {Amanda B}",

year = "2016",

month = jun,

day = "1",

doi = "10.1093/hmg/ddw094",

language = "English",

volume = "25",

pages = "2256--2268",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "11",

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T1 - Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms

AU - de la Hoya, Miguel

AU - Soukarieh, Omar

AU - López-perolio, Irene

AU - Vega, Ana

AU - Walker, Logan C

AU - Van Ierland, Yvette

AU - Baralle, Diana

AU - Santamariña, Marta

AU - Lattimore, Vanessa

AU - Wijnen, Juul

AU - Whiley, Philip

AU - Blanco, Ana

AU - Raponi, Michela

AU - Hauke, Jan

AU - Wappenschmidt, Barbara

AU - Becker, Alexandra

AU - Hansen, Thomas v O

AU - Behar, Raquel

AU - Investigators, Kconfab

AU - Niederacher, Diether

AU - Arnold, Norbert

AU - Dworniczak, Bernd

AU - Steinemann, Doris

AU - Faust, Ulrike

AU - Rubinstein, Wendy

AU - Hulick, Peter J

AU - Houdayer, Claude

AU - Caputo, Sandrine M.

AU - Castera, Laurent

AU - Pesaran, Tina

AU - Chao, Elizabeth

AU - Brewer, Carole

AU - Southey, Melissa C

AU - van Asperen, Christi J

AU - Singer, Christian F

AU - Sullivan, Jan

AU - Poplawski, Nicola

AU - Mai, Phuong L

AU - Peto, Julian

AU - Johnson, Nichola

AU - Burwinkel, Barbara

AU - Surowy, Harald M

AU - Bojesen, Stig E.

AU - Flyger, Henrik

AU - Lindblom, Annika

AU - Margolin, Sara

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Radice, Paolo

AU - Galastri, Laura

AU - Olson, Janet E

AU - Hallberg, Emily

AU - Giles, Graham

AU - Milne, Roger L

AU - Andrulis, Irene L

AU - Glendon, Gord

AU - Hall, Per

AU - Czene, Kamila

AU - Blows, Fiona

AU - Shah, Mitul

AU - Wang, Qin

AU - Dennis, Joe

AU - Michailidou, Kyriaki

AU - McGuffog, Lesley

AU - Bolla, Manjeet K

AU - Antoniou, Antonis C

AU - Easton, Douglas F

AU - Couch, Fergus J

AU - Tavtigian, Sean

AU - Vreeswijk, Maaike P

AU - Parsons, Michael

AU - Meeks, Huong D

AU - Martins, Alexandra

AU - Goldgar, David E

AU - Spurdle, Amanda B

PY - 2016/6/1

Y1 - 2016/6/1

N2 - A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A>C (IVS9-2A>C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A>C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 x 10-8. Our data indicate that c.594-2A>C is always in cis with c.641A>G. The spliceogenic effect of c.[594-2A>C;641A>G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A>C; 641A>G] caused exon 10 skipping, albeit not due to c.594-2A>C impairing the acceptor site but rather by c.641A>G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of70-80% truncating transcripts, and20-30% of in-frame D9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function. We confirm that BRCA1c.[594-2A>C;641A>G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes.

AB - A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A>C (IVS9-2A>C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A>C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 x 10-8. Our data indicate that c.594-2A>C is always in cis with c.641A>G. The spliceogenic effect of c.[594-2A>C;641A>G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A>C; 641A>G] caused exon 10 skipping, albeit not due to c.594-2A>C impairing the acceptor site but rather by c.641A>G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of70-80% truncating transcripts, and20-30% of in-frame D9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function. We confirm that BRCA1c.[594-2A>C;641A>G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes.

U2 - 10.1093/hmg/ddw094

DO - 10.1093/hmg/ddw094

M3 - Journal article

C2 - 27008870

SN - 0964-6906

VL - 25

SP - 2256

EP - 2268

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 11

ER -

Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms

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