Compendium of Cancer Genome Aberrations

GTS5:BRCA-related cancer predisposition syndrome (BRCA1, BRCA2): Difference between revisions

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|''BRCA1''||'''SNVs''' (frameshift, nonsense, pathogenic missense, canonical splice-site, synonymous splice-altering variants); '''CNVs''' (inactivating multi-exon deletions or duplications)||Multiple variant types lead to loss of BRCA1 function, resulting in impaired homologous recombination–mediated DNA double-strand break repair, defective DNA damage response, and genomic instability||Autosomal dominant cancer predisposition with incomplete penetrance and variable expressivity; rare biallelic pathogenic variants associated with Fanconi anemia–like phenotypes  
|''BRCA1''||'''SNVs''' (frameshift, nonsense, pathogenic missense, canonical splice-site, synonymous splice-altering variants); '''CNVs''' (inactivating multi-exon deletions or duplications)||Multiple variant types lead to loss of BRCA1 function, resulting in impaired homologous recombination–mediated DNA double-strand break repair, defective DNA damage response, and genomic instability||Autosomal dominant cancer predisposition with incomplete penetrance and variable expressivity; rare biallelic pathogenic variants associated with Fanconi anemia–like phenotypes  
|Heterozygous pathogenic variants confer increased lifetime risk of female and male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer. Estimated lifetime breast cancer risk ~60–80% and ovarian cancer risk ~35–45% in women [1,2]. Founder mutations reported in multiple populations, including c.68_69delAG (185delAG) and c.5266dupC (5382insC) [1,5]. Large genomic rearrangements represent a clinically significant subset of pathogenic BRCA1 variants and require copy-number–sensitive testing methods [4]. Molecular pathogenesis reflects failure of homologous recombination repair [3].
|Heterozygous pathogenic variants confer increased lifetime risk of female and male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer. Estimated lifetime breast cancer risk ~60–80% and ovarian cancer risk ~35–45% in women <ref name=":0">Petrucelli N, Daly MB, Pal T. ''BRCA1-'' and ''BRCA2''-Associated Hereditary Breast and Ovarian Cancer. 1998 Sep 4 [updated 2025 Mar 20]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews<sup>®</sup> [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 20301425.</ref><ref name=":1">Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips KA, Mooij TM, Roos-Blom MJ, Jervis S, van Leeuwen FE, Milne RL, Andrieu N, Goldgar DE, Terry MB, Rookus MA, Easton DF, Antoniou AC; BRCA1 and BRCA2 Cohort Consortium; McGuffog L, Evans DG, Barrowdale D, Frost D, Adlard J, Ong KR, Izatt L, Tischkowitz M, Eeles R, Davidson R, Hodgson S, Ellis S, Nogues C, Lasset C, Stoppa-Lyonnet D, Fricker JP, Faivre L, Berthet P, Hooning MJ, van der Kolk LE, Kets CM, Adank MA, John EM, Chung WK, Andrulis IL, Southey M, Daly MB, Buys SS, Osorio A, Engel C, Kast K, Schmutzler RK, Caldes T, Jakubowska A, Simard J, Friedlander ML, McLachlan SA, Machackova E, Foretova L, Tan YY, Singer CF, Olah E, Gerdes AM, Arver B, Olsson H. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA. 2017 Jun 20;317(23):2402-2416. doi: 10.1001/jama.2017.7112. PMID: 28632866.</ref>. Founder mutations reported in multiple populations, including c.68_69delAG (185delAG) and c.5266dupC (5382insC) <ref name=":0" /><ref name=":2">Neuhausen S, Gilewski T, Norton L et al. Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nat Genet 1996; 13: 126–128.</ref><ref name=":3">Ferla R, Calò V, Cascio S, Rinaldi G, Badalamenti G, Carreca I, Surmacz E, Colucci G, Bazan V, Russo A. Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol. 2007 Jun;18 Suppl 6:vi93-8. doi: 10.1093/annonc/mdm234. PMID: 17591843.</ref>. Large genomic rearrangements represent a clinically significant subset of pathogenic BRCA1 variants and require copy-number–sensitive testing methods<ref name=":4">Sluiter MD, van Rensburg EJ. Large genomic rearrangements of the BRCA1 and BRCA2 genes: review of the literature and report of a novel BRCA1 mutation. Breast Cancer Res Treat. 2011 Jan;125(2):325-49. doi: 10.1007/s10549-010-0817-z. Epub 2010 Mar 16. PMID: 20232141.</ref>. Molecular pathogenesis reflects failure of homologous recombination repair <ref name=":5">Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002 Jan 25;108(2):171-82. doi: 10.1016/s0092-8674(02)00615-3. PMID: 11832208.</ref>.
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|''BRCA2''
|''BRCA2''
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|Multiple variant types leading to '''loss of BRCA2 function''', resulting in defective '''homologous recombination–mediated DNA double-strand break repair''', genomic instability, and cancer susceptibility
|Multiple variant types leading to '''loss of BRCA2 function''', resulting in defective '''homologous recombination–mediated DNA double-strand break repair''', genomic instability, and cancer susceptibility
|'''Autosomal dominant''' cancer predisposition with '''incomplete penetrance''' and variable expressivity; '''autosomal recessive''' when biallelic, causing '''Fanconi anemia subtype D1 (FA-D1)'''
|'''Autosomal dominant''' cancer predisposition with '''incomplete penetrance''' and variable expressivity; '''autosomal recessive''' when biallelic, causing '''Fanconi anemia subtype D1 (FA-D1)'''
|Heterozygous pathogenic variants confer increased lifetime risk of '''female and male breast, ovarian, pancreatic, prostate, and melanoma''' cancers. Estimated female breast cancer risk ~'''45–70%''', ovarian cancer ~'''10–30%''' . Founder mutations include '''c.5946delT (6174delT)''' in Ashkenazi Jewish populations . '''Large genomic rearrangements''' represent a clinically significant subset of pathogenic variants and may be missed by sequencing-only assays . Biallelic pathogenic variants result in '''FA-D1''', characterized by congenital anomalies, bone marrow failure, and early-onset malignancies
|Heterozygous pathogenic variants confer increased lifetime risk of '''female and male breast, ovarian, pancreatic, prostate, and melanoma''' cancers. Estimated female breast cancer risk ~'''45–70%''', ovarian cancer ~'''10–30%'''<ref name=":0" /><ref name=":1" /> . Founder mutations include '''c.5946delT (6174delT)''' in Ashkenazi Jewish populations<ref name=":0" /><ref name=":6">Oddoux C, Struewing JP, Clayton CM, Neuhausen S, Brody LC, Kaback M, Haas B, Norton L, Borgen P, Jhanwar S, Goldgar D, Ostrer H, Offit K. The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet. 1996 Oct;14(2):188-90. doi: 10.1038/ng1096-188. PMID: 8841192.</ref> . '''Large genomic rearrangements''' represent a clinically significant subset of pathogenic variants and may be missed by sequencing-only assays . Biallelic pathogenic variants result in '''FA-D1''', characterized by congenital anomalies, bone marrow failure, and early-onset malignancies
|}
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==Genetic Abnormalities: Somatic==
==Genetic Abnormalities: Somatic==
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https://clinicalgenome.org/affiliation/50087/
https://clinicalgenome.org/affiliation/50087/
==References==
==References==
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span>
<ref name=":0" />Petrucelli N, Daly MB, Pal T. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. 1998 Sep 4 [updated 2025 Mar 20]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 20301425.
 
<ref name=":1" />Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips KA, Mooij TM, Roos-Blom MJ, Jervis S, van Leeuwen FE, Milne RL, Andrieu N, Goldgar DE, Terry MB, Rookus MA, Easton DF, Antoniou AC; BRCA1 and BRCA2 Cohort Consortium; McGuffog L, Evans DG, Barrowdale D, Frost D, Adlard J, Ong KR, Izatt L, Tischkowitz M, Eeles R, Davidson R, Hodgson S, Ellis S, Nogues C, Lasset C, Stoppa-Lyonnet D, Fricker JP, Faivre L, Berthet P, Hooning MJ, van der Kolk LE, Kets CM, Adank MA, John EM, Chung WK, Andrulis IL, Southey M, Daly MB, Buys SS, Osorio A, Engel C, Kast K, Schmutzler RK, Caldes T, Jakubowska A, Simard J, Friedlander ML, McLachlan SA, Machackova E, Foretova L, Tan YY, Singer CF, Olah E, Gerdes AM, Arver B, Olsson H. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA. 2017 Jun 20;317(23):2402-2416. doi: 10.1001/jama.2017.7112. PMID: 28632866.
 
<ref name=":2" />Neuhausen S, Gilewski T, Norton L et al. Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nat Genet 1996; 13: 126–128.
 
<ref name=":3" />Ferla R, Calò V, Cascio S, Rinaldi G, Badalamenti G, Carreca I, Surmacz E, Colucci G, Bazan V, Russo A. Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol. 2007 Jun;18 Suppl 6:vi93-8. doi: 10.1093/annonc/mdm234. PMID: 17591843.
 
<ref name=":4" />Sluiter MD, van Rensburg EJ. Large genomic rearrangements of the BRCA1 and BRCA2 genes: review of the literature and report of a novel BRCA1 mutation. Breast Cancer Res Treat. 2011 Jan;125(2):325-49. doi: 10.1007/s10549-010-0817-z. Epub 2010 Mar 16. PMID: 20232141.
 
<ref name=":5" />Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002 Jan 25;108(2):171-82. doi: 10.1016/s0092-8674(02)00615-3. PMID: 11832208.
 
<ref name=":6" />Oddoux C, Struewing JP, Clayton CM, Neuhausen S, Brody LC, Kaback M, Haas B, Norton L, Borgen P, Jhanwar S, Goldgar D, Ostrer H, Offit K. The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet. 1996 Oct;14(2):188-90. doi: 10.1038/ng1096-188. PMID: 8841192.
 
 
==Notes==
==Notes==
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<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.  
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