Compendium of Cancer Genome Aberrations

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

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[[GTS5:Table_of_Contents|Genetic Tumour Syndromes (Who Classification, 5th ed.)]]
[[GTS5:Table_of_Contents|Genetic Tumour Syndromes (Who Classification, 5th ed.)]]
==Primary Author(s)*==
==Primary Author(s)*==
<br />Parisa Kargaran, Ph.D.
Parisa Kargaran, Ph.D.
==WHO Classification of Disease==
==WHO Classification of Disease==


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==Definition/Description of Disease==
==Definition/Description of Disease==
Put your text here <span style="color:#0070C0">(''Instructions: Include a brief general clinical description, diagnostic criteria, and differential diagnosis if applicable. Include disease context relative to other WHO classification categories, i.e. describe any information relevant to the genetic aspects of the disease from all WHO classification books in which the syndrome is described.'')</span>
'''BRCA1 and BRCA2 Associated Hereditary Cancer Predisposition'''
 
''BRCA1'' (17q21.31) and ''BRCA2'' (13q13.1) are tumor-suppressor genes that encode key components of the homologous recombination (HR) DNA double-strand break repair pathway. ''BRCA1'' plays a central role in DNA damage sensing, checkpoint activation, and repair pathway choice, while ''BRCA2'' is essential for ''RAD51'' loading and stabilization at sites of DNA damage. Together, ''BRCA1'' and ''BRCA2'' maintain genomic stability and prevent accumulation of chromosomal aberrations. In the heterozygous state, germline pathogenic variants in ''BRCA1'' or ''BRCA2'' are associated with autosomal dominant hereditary breast and ovarian cancer (HBOC) syndrome, with incomplete penetrance and variable expressivity observed. Affected individuals have substantially increased lifetime risks for female breast and ovarian cancers, with additional risks for male breast, prostate, pancreatic, and melanoma cancers, particularly in ''BRCA2'' carriers. Disease onset is often earlier than for sporadic counterparts, and tumors frequently demonstrate a homologous recombination deficient (HRD) molecular phenotype. This syndrome is classified across multiple WHO Tumour Classification volumes under hereditary cancer predisposition syndromes affecting the breast, ovary, prostate, and pancreas. In the biallelic state, pathogenic variants in ''BRCA2'' (also known as FANCD1) cause Fanconi anemia subtype D1, a rare autosomal recessive chromosomal instability disorder characterized by congenital anomalies, growth retardation, progressive bone marrow failure, and early onset malignancies, including acute leukemia and solid tumors in childhood. Biallelic pathogenic variants in ''BRCA1'' are exceedingly rare and have been associated with Fanconi anemia like phenotypes with developmental abnormalities and pediatric cancer susceptibility. These conditions fall within the WHO classification of inherited bone marrow failure and genomic instability syndromes. Diagnosis of ''BRCA1/BRCA2'' associated hereditary cancer predisposition is established through germline molecular genetic testing, typically using sequencing with deletion/duplication analysis. Genetic testing of tumors post therapy (particularly PARP inhibitor therapy) may reveal secondary somatic inactivation or reversion mutations, which have therapeutic implications. Differential diagnosis includes other hereditary breast and ovarian cancer syndromes involving genes in the HR and DNA damage response pathways (e.g., ''PALB2, ATM, CHEK2, RAD51C/D'') as well as sporadic cancers with somatic HR deficiency.
 
==Epidemiology/Prevalence==
==Epidemiology/Prevalence==
Put your text here
 
=== ''BRCA1'' ===
 
* '''Incidence / Carrier frequency:''' Germline pathogenic variants in ''BRCA1'' occur in approximately 1 in 400–500 individuals in the general population, with higher prevalence in certain founder populations (e.g., ~1 in 40 in Ashkenazi Jewish individuals).
* '''Cancer risk''' (heterozygous carriers): Heterozygous pathogenic variants in ''BRCA1'' are associated with a high lifetime risk of breast and ovarian cancer, with incomplete penetrance and variable expressivity.
* '''Lifetime cancer risks:'''
** Female breast cancer: ~60–80% lifetime risk (relative risk ~7–10 fold compared with the general population)
** Ovarian cancer: ~35–45% lifetime risk
** Male breast cancer: Increased risk, though substantially lower than in females
** Other cancers: Increased risk of prostate and pancreatic cancers
* '''Tumor characteristics:''' ''BRCA1'' associated breast cancers are enriched for triple negative breast cancer (TNBC) and frequently display a homologous recombination deficient (HRD) phenotype.
 
=== ''BRCA2'' ===
 
* '''Incidence / Carrier frequency:''' Germline pathogenic variants in ''BRCA2'' are present in approximately 1 in 400–500 individuals in the general population, with increased prevalence in founder populations (e.g., Ashkenazi Jewish).
* '''Cancer risk (heterozygous carriers):''' Heterozygous pathogenic variants in ''BRCA2'' confer substantially increased risks for breast, ovarian, pancreatic, prostate, and male breast cancers, with incomplete penetrance.
* '''Lifetime cancer risks:'''
** Female breast cancer: ~45–70% lifetime risk (relative risk ~5–7-fold)
** Ovarian cancer: ~10–30% lifetime risk
** Male breast cancer: Significantly increased compared with the general population
** Prostate cancer: Elevated risk, often with earlier onset and aggressive features
** Pancreatic cancer: Moderately increased risk
* '''Tumor characteristics:''' ''BRCA2'' associated breast cancers are more often hormone receptor positive, though HRD remains a defining molecular feature.
 
==Genetic Abnormalities: Germline==
==Genetic Abnormalities: Germline==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Describe germline alteration(s) that cause the syndrome. In the notes, include additional details about most common mutations including founder mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetics-related information. If multiple causes of the syndrome, include relative prevalence of genetic contributions to that syndrome. Please include references throughout the table. Do not delete the table.'')</span>
{| class="wikitable sortable"
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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 <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>.
|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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==Genetic Abnormalities: Somatic==
==Genetic Abnormalities: Somatic==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Describe significant second hit mutations, or somatic variants that present as a germline syndrome. In the notes, include details about most common mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetic-related information. Please include references throughout the table. Do not delete the table.'')</span>
{| class="wikitable sortable"
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!Notes
!Notes
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|''BRCA1''||Biallelic inactivation (second hit) including somatic SNVs/indels, copy-neutral LOH, focal or arm-level deletion, promoter hypermethylation, or complex structural rearrangements||In individuals with a germline pathogenic BRCA1 variant, tumor development follows a two-hit mechanism. Somatic loss of the remaining wild-type allele results in complete BRCA1 deficiency, impaired homologous recombination DNA repair, genomic instability, and carcinogenesis||Somatic, tumor-specific event; not inherited. Results in a homologous recombination–deficient (HRD) tumor phenotype
|''BRCA1''||Biallelic inactivation (second hit) including somatic SNVs/indels, copy-neutral LOH, focal or arm-level deletion, promoter hypermethylation, or complex structural rearrangements||In individuals with a germline pathogenic ''BRCA1'' variant, tumor development follows a two-hit mechanism. Somatic loss of the remaining wild-type allele results in complete BRCA1 deficiency, impaired homologous recombination DNA repair, genomic instability, and carcinogenesis||Somatic, tumor-specific event; not inherited. Results in a homologous recombination–deficient (HRD) tumor phenotype
|Common in BRCA1-associated breast and ovarian cancers. Biallelic loss is associated with increased sensitivity to platinum chemotherapy and PARP inhibitors <ref name=":0" /><ref name=":10">Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer. 2011 Dec 23;12(1):68-78. doi: 10.1038/nrc3181. PMID: 22193408; PMCID: PMC4972490.</ref>. Promoter hypermethylation represents a frequent non-sequence–based second hit in BRCA1-driven tumors<ref name=":11">Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst. 2000 Apr 5;92(7):564-9. doi: 10.1093/jnci/92.7.564. PMID: 10749912.</ref>
|Common in ''BRCA1''-associated breast and ovarian cancers. Biallelic loss is associated with increased sensitivity to platinum chemotherapy and PARP inhibitors <ref name=":0" /><ref name=":10">Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer. 2011 Dec 23;12(1):68-78. doi: 10.1038/nrc3181. PMID: 22193408; PMCID: PMC4972490.</ref>. Promoter hypermethylation represents a frequent non-sequence–based second hit in ''BRCA1''-driven tumors<ref name=":11">Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst. 2000 Apr 5;92(7):564-9. doi: 10.1093/jnci/92.7.564. PMID: 10749912.</ref>
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|''BRCA1''
|''BRCA1''
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|''BRCA2''
|''BRCA2''
|Biallelic inactivation (second hit) including somatic SNVs/indels, copy-neutral LOH, focal or whole-arm deletion, or complex structural rearrangements
|Biallelic inactivation (second hit) including somatic SNVs/indels, copy-neutral LOH, focal or whole-arm deletion, or complex structural rearrangements
|In individuals with a germline pathogenic BRCA2 variant, tumorigenesis follows a two-hit mechanism. Somatic loss of the remaining wild-type allele leads to complete loss of BRCA2 function, defective homologous recombination repair, genomic instability, and tumor development
|In individuals with a germline pathogenic ''BRCA2'' variant, tumorigenesis follows a two-hit mechanism. Somatic loss of the remaining wild-type allele leads to complete loss of BRCA2 function, defective homologous recombination repair, genomic instability, and tumor development
|Somatic event occurs in tumor tissue only; not inherited. Tumor phenotype shows homologous recombination deficiency (HRD)
|Somatic event occurs in tumor tissue only; not inherited. Tumor phenotype shows homologous recombination deficiency (HRD)
|Common mechanism in BRCA2-associated breast, ovarian, pancreatic, and prostate cancers. Presence of biallelic loss predicts sensitivity to platinum chemotherapy and PARP inhibitors<ref name=":0" /><ref name=":10" />
|Common mechanism in ''BRCA2''-associated breast, ovarian, pancreatic, and prostate cancers. Presence of biallelic loss predicts sensitivity to platinum chemotherapy and PARP inhibitors<ref name=":0" /><ref name=":10" />
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|''BRCA2''
|''BRCA2''
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==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
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!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
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|BRCA1; Loss-of-function germline or somatic mutations
|''BRCA1''; Loss-of-function germline or somatic mutations
|Homologous recombination (HR) DNA double-strand break repair; DNA damage response
|Homologous recombination (HR) DNA double-strand break repair; DNA damage response
|Defective DNA repair leading to genomic instability and chromosomal aberrations; increased cancer susceptibility. Tumors demonstrate homologous recombination deficiency (HRD) and sensitivity to platinum agents and PARP inhibitors<ref name=":0" /><ref name=":5" /><ref name=":10" />
|Defective DNA repair leading to genomic instability and chromosomal aberrations; increased cancer susceptibility. Tumors demonstrate homologous recombination deficiency (HRD) and sensitivity to platinum agents and PARP inhibitors<ref name=":0" /><ref name=":5" /><ref name=":10" />
|-
|-
|BRCA2; Loss-of-function germline or somatic mutations
|''BRCA2''; Loss-of-function germline or somatic mutations
|Homologous recombination DNA repair (RAD51 loading and stabilization)
|Homologous recombination DNA repair (RAD51 loading and stabilization)
|Impaired repair of DNA double-strand breaks, genomic instability, and tumorigenesis; HRD phenotype with therapeutic vulnerability to PARP inhibition<ref name=":0" /><ref name=":5" /><ref name=":10" />
|Impaired repair of DNA double-strand breaks, genomic instability, and tumorigenesis; HRD phenotype with therapeutic vulnerability to PARP inhibition<ref name=":0" /><ref name=":5" /><ref name=":10" />
|-
|-
|PALB2; Inactivating mutations
|''PALB2''; Inactivating mutations
|BRCA1–BRCA2–PALB2 DNA repair complex (HR pathway)
|BRCA1–BRCA2–PALB2 DNA repair complex (HR pathway)
|Disruption of BRCA1–BRCA2 interaction, defective homologous recombination, and increased cancer risk similar to BRCA2-associated tumors<ref name=":0" /><ref name=":15">Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res. 2010 Oct 1;70(19):7353-9. doi: 10.1158/0008-5472.CAN-10-1012. Epub 2010 Sep 21. PMID: 20858716; PMCID: PMC2948578.</ref>
|Disruption of BRCA1–BRCA2 interaction, defective homologous recombination, and increased cancer risk similar to ''BRCA2''-associated tumors<ref name=":0" /><ref name=":15">Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res. 2010 Oct 1;70(19):7353-9. doi: 10.1158/0008-5472.CAN-10-1012. Epub 2010 Sep 21. PMID: 20858716; PMCID: PMC2948578.</ref>
|-
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|ATM; Inactivating mutations
|''ATM''; Inactivating mutations
|DNA damage sensing and signaling (ATM–CHK2 pathway)
|DNA damage sensing and signaling (ATM–CHK2 pathway)
|Impaired activation of DNA damage checkpoints, defective response to double-strand breaks, accumulation of genomic damage, and cancer predisposition<ref name=":16">Shiloh, Y., Ziv, Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. ''Nat Rev Mol Cell Biol'' '''14''', 197–210 (2013). <nowiki>https://doi.org/10.1038/nrm3546</nowiki></ref>
|Impaired activation of DNA damage checkpoints, defective response to double-strand breaks, accumulation of genomic damage, and cancer predisposition<ref name=":16">Shiloh, Y., Ziv, Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. ''Nat Rev Mol Cell Biol'' '''14''', 197–210 (2013). <nowiki>https://doi.org/10.1038/nrm3546</nowiki></ref>
|-
|-
|CHEK2; Inactivating mutations
|''CHEK2''; Inactivating mutations
|Cell-cycle checkpoint control and DNA damage response
|Cell-cycle checkpoint control and DNA damage response
|Failure of G1/S and G2/M checkpoint arrest following DNA damage, allowing propagation of genomic instability<ref name=":16" />
|Failure of G1/S and G2/M checkpoint arrest following DNA damage, allowing propagation of genomic instability<ref name=":16" />
|-
|-
|TP53; Inactivating or dominant-negative mutations
|''TP53''; Inactivating or dominant-negative mutations
|Cell-cycle regulation, apoptosis, genome integrity
|Cell-cycle regulation, apoptosis, genome integrity
|Loss of DNA damage–induced cell-cycle arrest and apoptosis, enabling survival and expansion of genetically unstable cells<ref name=":5" /><ref name=":16" />
|Loss of DNA damage–induced cell-cycle arrest and apoptosis, enabling survival and expansion of genetically unstable cells<ref name=":5" /><ref name=":16" />
|-
|-
|RAD51C / RAD51D; Inactivating mutations
|''RAD51C'' / ''RAD51D''; Inactivating mutations
|Homologous recombination DNA repair
|Homologous recombination DNA repair
|mpaired strand invasion and repair of DNA double-strand breaks, contributing to HRD and hereditary cancer susceptibility<ref name=":0" /><ref name=":17">Loveday, C., Turnbull, C., Ramsay, E. et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet 43, 879–882 (2011). <nowiki>https://doi.org/10.1038/ng.893</nowiki></ref>
|mpaired strand invasion and repair of DNA double-strand breaks, contributing to HRD and hereditary cancer susceptibility<ref name=":0" /><ref name=":17">Loveday, C., Turnbull, C., Ramsay, E. et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet 43, 879–882 (2011). <nowiki>https://doi.org/10.1038/ng.893</nowiki></ref>
|}
|}
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==
Put your text here <span style="color:#0070C0">(''Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.'')</span>
Germline diagnosis of ''BRCA1'' and ''BRCA2'' associated hereditary cancer predisposition is established by molecular genetic testing performed on constitutional DNA (e.g., blood or saliva). Testing strategies must detect both sequence variants and copy number alterations, as pathogenic variants span multiple variant classes.
==Additional Information==
Put your text here
==Links==
https://clinicalgenome.org/affiliation/50087/
==References==
<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.
'''Primary testing approaches:''' Next-generation sequencing (NGS), including multigene hereditary cancer panels or genome/exome sequencing, is the first-line method for detection of single-nucleotide variants (SNVs), small insertions/deletions, and splice-site variants in ''BRCA1'' and ''BRCA2''. Copy-number variant (CNV) analysis, performed using NGS-based CNV calling, multiplex ligation-dependent probe amplification (MLPA), or array-based methods, is required to detect large genomic rearrangements, including multi-exon deletions or duplications, which represent a clinically significant subset of pathogenic variants.


<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.
'''Supplementary and confirmatory methods:''' MLPA or other targeted deletion/duplication assays are commonly used to confirm suspected CNVs or when sequencing-only approaches are insufficient. Sanger sequencing may be employed for targeted variant confirmation or cascade testing in at-risk relatives once a familial pathogenic variant has been identified.


<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.
'''Tumor testing:''' Tumor sequencing may identify somatic ''BRCA1/BRCA2'' alterations, loss of heterozygosity, or reversion mutations, which have implications for therapeutic selection and resistance, particularly in the context of PARP inhibitor therapy. Identification of a pathogenic ''BRCA1/BRCA2'' variant in tumor tissue should prompt confirmatory germline testing to distinguish hereditary from purely somatic events.


<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.
==Additional Information ''BRCA1'' and ''BRCA2''==


<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.
* '''Founder mutations:''' Multiple recurrent pathogenic variants demonstrate strong population specific founder effects, most notably c.68_69delAG (185delAG) and c.5266dupC (5382insC) in ''BRCA1'', and c.5946delT (6174delT) in ''BRCA2'', particularly among individuals of Ashkenazi Jewish ancestry. Additional founder variants have been reported in Icelandic, Dutch, and other geographically or ethnically defined populations, underscoring the importance of ancestry-informed testing strategies.


<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.
* '''Genotype–phenotype correlations:''' Although penetrance is variable, ''BRCA1'' pathogenic variants are disproportionately associated with triple-negative breast cancer, whereas ''BRCA2'' pathogenic variants are more commonly linked to hormone receptor–positive breast cancer and confer a higher risk of male breast and prostate cancers. These genotype-phenotype differences have implications for clinical presentation, surveillance, and therapeutic decision-making.


<ref name=":7" />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.
* '''Therapeutic implications:''' Tumors with biallelic inactivation of ''BRCA1'' or ''BRCA2'' exhibit homologous recombination deficiency (HRD), resulting in increased sensitivity to platinum-based chemotherapy and PARP inhibitors. However, acquisition of secondary somatic reversion mutations that restore gene function represents a well-established mechanism of acquired therapeutic resistance, particularly following prolonged treatment exposure.


<ref name=":8" />Alter BP, Rosenberg PS, Brody LC. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet. 2007 Jan;44(1):1-9. doi: 10.1136/jmg.2006.043257. Epub 2006 Jul 6. PMID: 16825431; PMCID: PMC2597904.
* '''Risk management considerations:''' Identification of germline pathogenic variants in ''BRCA1'' or ''BRCA2'' has substantial implications for personalized cancer risk assessment, implementation of enhanced surveillance protocols, consideration of risk-reducing surgical interventions, and cascade testing of at risk relatives.


<ref name=":9" />Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, D'Andrea AD. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002 Jul 26;297(5581):606-9. doi: 10.1126/science.1073834. Epub 2002 Jun 13. PMID: 12065746.
* '''Overlap with other syndromes:''' ''BRCA1'' and ''BRCA2'' associated hereditary cancer predisposition shares molecular and clinical features with other DNA damage response and homologous recombination repair disorders, including syndromes caused by pathogenic variants in ''PALB2, ATM, CHEK2,'' and ''RAD51C/D''. These genes should be considered in differential diagnosis and comprehensive hereditary cancer panel testing.


<ref name=":10" />Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer. 2011 Dec 23;12(1):68-78. doi: 10.1038/nrc3181. PMID: 22193408; PMCID: PMC4972490.
==Links==
https://clinicalgenome.org/affiliation/50087/


<ref name=":11" />Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst. 2000 Apr 5;92(7):564-9. doi: 10.1093/jnci/92.7.564. PMID: 10749912.
https://www.ncbi.nlm.nih.gov/clinvar/?term=%22BRCA1%22%5BGENE%5D


<ref name=":12" />Norquist B, Wurz KA, Pennil CC, Garcia R, Gross J, Sakai W, Karlan BY, Taniguchi T, Swisher EM. Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J Clin Oncol. 2011 Aug 1;29(22):3008-15. doi: 10.1200/JCO.2010.34.2980. Epub 2011 Jun 27. PMID: 21709188; PMCID: PMC3157963.
https://www.ncbi.nlm.nih.gov/clinvar/?term=%22BRCA2%22&#x5B;GENE&#x5D;
 
<ref name=":13" />Goodall J, Mateo J, Yuan W, Mossop H, Porta N, Miranda S, Perez-Lopez R, Dolling D, Robinson DR, Sandhu S, Fowler G, Ebbs B, Flohr P, Seed G, Rodrigues DN, Boysen G, Bertan C, Atkin M, Clarke M, Crespo M, Figueiredo I, Riisnaes R, Sumanasuriya S, Rescigno P, Zafeiriou Z, Sharp A, Tunariu N, Bianchini D, Gillman A, Lord CJ, Hall E, Chinnaiyan AM, Carreira S, de Bono JS; TOPARP-A investigators. Circulating Cell-Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition. Cancer Discov. 2017 Sep;7(9):1006-1017. doi: 10.1158/2159-8290.CD-17-0261. Epub 2017 Apr 27. PMID: 28450425; PMCID: PMC6143169.
 
<ref name=":14" />Edwards SL, Brough R, Lord CJ, Natrajan R, Vatcheva R, Levine DA, Boyd J, Reis-Filho JS, Ashworth A. Resistance to therapy caused by intragenic deletion in BRCA2. Nature. 2008 Feb 28;451(7182):1111-5. doi: 10.1038/nature06548. Epub 2008 Feb 10. PMID: 18264088.
 
<ref name=":15" />Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res. 2010 Oct 1;70(19):7353-9. doi: 10.1158/0008-5472.CAN-10-1012. Epub 2010 Sep 21. PMID: 20858716; PMCID: PMC2948578.
 
<ref name=":16" />Shiloh, Y., Ziv, Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol 14, 197–210 (2013). <nowiki>https://doi.org/10.1038/nrm3546</nowiki>
 
<ref name=":17" />Loveday, C., Turnbull, C., Ramsay, E. et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet 43, 879–882 (2011). <nowiki>https://doi.org/10.1038/ng.893</nowiki>


==References==
[[Category:GTS5]]
[[Category:DISEASE]]
<references />
==Notes==
==Notes==
<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.  
<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.  


Prior Author(s):  
Prior Author(s):  
[[Category:GTS5]]
[[Category:DISEASE]]
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